IMR Press / FBL / Volume 29 / Issue 5 / DOI: 10.31083/j.fbl2905184
Open Access Review
From Tumor to Bone: Growth Factor Receptors as Key Players in Cancer Metastasis
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1 Department of Anatomy, College of Medicine, Alfaisal University, 1153 Riyadh, Saudi Arabia
*Correspondence: kmohammad@alfaisal.edu (Khalid Said Mohammad)
Front. Biosci. (Landmark Ed) 2024, 29(5), 184; https://doi.org/10.31083/j.fbl2905184
Submitted: 28 December 2023 | Revised: 31 March 2024 | Accepted: 12 April 2024 | Published: 13 May 2024
Copyright: © 2024 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.
Abstract

This review article explores the intricate correlation between growth factors and bone metastases, which play a crucial role in the development of several types of malignancies, namely breast, prostate, lung, and renal cancers. The focal point of our discussion is on crucial receptors for growth factors, including Epidermal Growth Factor Receptor (EGFR), Transforming Growth Factor-β (TGFβ), Vascular Endothelial Growth Factor Receptor (VEGFR), and Fibroblast Growth Factor Receptor (FGFR). These receptors, which are essential for cellular activities including growth, differentiation, and survival, have important involvement in the spread of cancer and the interactions between tumors and the bone environment. We discuss the underlying mechanisms of bone metastases, with a specific emphasis on the interaction between growth factor receptors and the bone microenvironment. EGFR signaling specifically enhances the process of osteoclast development and the formation of osteolytic lesions, especially in breast and lung malignancies. TGFβ receptors have a role in both osteolytic and osteoblastic metastases by releasing TGFβ, which attracts cancer cells and promotes bone remodeling. This is a crucial element in the spread of prostate cancer to the bones. The functions of FGFR and VEGFR in the processes of bone formation and tumor angiogenesis, respectively, highlight the complex and diverse nature of these interactions. The review emphasizes the possibility of targeted therapeutics targeting these receptors to interrupt the cycle of tumor development and bone degradation. Therapeutic approaches include focusing on the VEGF/VEGFR, EGF/EGFR, FGF/FGFR, and TGFβ/TGFβR pathways. These include a variety of compounds, such as small molecule inhibitors and monoclonal antibodies, which have shown potential to interfere with tumor-induced alterations in bone. The text discusses clinical trials and preclinical models, offering insights into the effectiveness and constraints of various treatments. Ultimately, this study provides a succinct but thorough summary of the present knowledge and treatment strategies focused on growth factor receptors in bone metastases. This highlights the significance of comprehending the signaling of growth factor receptors in the microenvironment where tumors spread to the bones, as well as the possibility of using targeted therapies to enhance the results for cancer patients with bone metastases. The advancement of treating bone metastases hinges on the development of treatments that specifically target the intricate relationships between malignancies and bone.

Keywords
transforming growth factor-β (TGFβ)
epidermal growth factor (EGF)
vascular endothelial growth factor (VEGF)
fibroblast growth factor (FGF)
bone metastases
targeted therapies
1. Introduction

The process of metastases is defined as cancer cells detaching from the original or primary tumor and migrating to a distant site. Bone metastases are particularly common in certain types of solid tumors such as breast, prostate, renal and lung cancer [1]. Bone metastases represent a significant clinical challenge, and the patient suffers from pain, pathological fracture and hypercalcemia, collectively known as skeletal-related events (SREs). Despite the recent advancement in cancer treatment, bone metastases are incurable. Treatment is typically palliative, focusing on pain management, maintaining mobility, and preventing SREs. Therapies may include radiation therapy, bisphosphonates, surgery, and targeted therapies [2, 3, 4].

The mechanism of bone metastasis involves complex interactions between cancer cells and the resident cells of the bone microenvironment. When cancer cells seed into the bone, it disrupts normal bone remodeling and the balance between bone-forming osteoblasts and bone-resorbing osteoclasts [5, 6]. Depending on the type of cancer, metastases can lead to either osteolytic lesions (bone destruction), which are mainly seen in breast, renal, and lung cancers, or osteoblastic lesions (bone formation), commonly associated with prostate cancer. These bone lesions represent a spectrum of the disease, and mixed osteolytic and osteoblastic lesions are widely seen in X-rays in many of these cancer patients.

Growth factor receptors are integral membrane proteins that regulate cellular processes, including proliferation, differentiation, and survival. These receptors are especially important in bone metastases because they play a part in the metastatic cascade and the tumor-bone microenvironment [7]. Bone metastases occur when cancer cells from primary sites, like the breast, prostate, or lung, migrate to the bone, a process facilitated by interactions between growth factor receptors and their ligands. The metastatic cascade is a complex process where aggressive cancer cells leave the primary tumor, enter the bloodstream, and form new tumors in distant organs. The steps of the cancer metastatic cascade involve tumor cell detachment, migration, invasion, intravasation, circulation, extravasation, and colonization. Tumor cells detach from neighboring cells and undergo migration either as single cells or as cell clusters [8]. They then invade surrounding tissues and intravasate into the bloodstream [9]. Circulating tumor cells (CTCs) travel through the bloodstream and eventually extravasate into distant organs. Once in the new site, tumor cells establish a metastatic focus and form secondary tumors [10]. Recent references for these steps include studies on the signaling pathways involved in metastasis formation Growth factors like epidermal growth factor receptor (EGFR), Transforming Growth Factor-β (TGFβ), and fibroblast growth factor (FGF) play crucial roles in this process. EGFR is pivotal in cell proliferation and survival, while TGFβ and FGF are key in cell transformation, migration, and the modulation of the tumor microenvironment.

Recent studies highlight the significance of these growth factors in metastasis. For instance, TGFβ signaling pathways have been identified as critical in the transformation of normal cells into aggressively metastatic ones, indicating its dual role in tumor suppression and promotion depending on the context and cancer stage [11, 12]. Similarly, FGF23, produced by bone cells, plays a role in renal phosphate reabsorption and vitamin D metabolism, indirectly influencing cancer metabolism and growth [13]. The involvement of Matrix Metalloproteinases (MMPs), which are regulated by these growth factors, further underscores their importance in the initial phases of cancer and the establishment of metastatic niches.

The EGFR family, the TGFβ receptor family, the FGFR receptors and VEGFR are the main groups of growth factor receptors that play a major role in bone metastases. EGFR signaling promotes osteoclast differentiation and bone resorption [14], contributing to the osteolytic lesions frequently seen in bone metastases, especially in breast and lung cancers. EGFR antagonists, like tyrosine kinase inhibitors, have shown potential in mitigating these effects [15, 16].

On the other hand, TGFβ receptors play a part in both osteolytic and osteoblastic metastatic processes [12, 17]. When bone remodels, it releases TGFβ from the bone matrix. This protein acts as a chemotactic factor, drawing cancer cells to the bone microenvironment. It also stimulates cancer cells to produce other factors that further drive bone destruction and new bone formation, as seen in prostate cancer metastases. Inhibiting TGFβ signaling is thus a promising therapeutic strategy for managing bone metastases [12, 18].

Activation of the FGFR signaling pathway impacts the bone microenvironment in metastatic cancer by altering the interactions between cancer cells and bone stromal cells [19]. When activated, FGFR results in elevated production of cytokines and growth factors, like IL-6 family members, that attach to receptors on bone stromal cells and trigger subsequent signaling pathways, such as STAT3. Activating FGFR signaling in osteoblasts leads to elevated expression of molecules such as receptor activator of nuclear factor-kappa B ligand (RANKL), macrophage colony-stimulating factor (M-CSF), and osteoprotegerin (OPG). FGFR inhibitors have been demonstrated to reduce osteoclastogenesis and tumor-induced osteolysis in a breast cancer bone metastasis mice model [19]. VEGFR plays a significant role in the development of bone metastases. VEGF-A and its receptors, including VEGFR-1 and VEGFR-2, are involved in both osteoclastogenesis and tumor growth [20]. Inhibition of VEGFR-2 reduces osteosarcoma cell metastatic abilities and attenuates migration and invasion [21]. VEGFR-1 activation in tumor cells induces cell chemotaxis and extracellular matrix invasion, contributing to tumor progression and metastasis [5]. Targeting VEGFR-1 or VEGFR-2 expressing cells can inhibit tumor progression in bone and reduce the number of tumor-associated osteoclasts. Studying the growth factors in bone metastases is of utmost importance due to their pivotal role in the progression of cancer and the dissemination of metastases, particularly in the skeletal system. Growth factors such as EGF, TGFβ, and FGF coordinate a wide array of cellular activities that are crucial for the survival and proliferation of cancer cells, as well as for the intricate interplay between these cells and the bone microenvironment. This intricate relationship not only promotes the formation of metastases but also impacts the outcomes of therapeutic interventions. Acquiring an extensive understanding of the mechanisms by which these growth factor’s function may open up the possibility for the development of targeted therapies that can potentially disrupt the harmful cycle of bone metastases and tumor growth, thereby improving the prognosis for patients. This field of investigation holds the promise of uncovering novel therapeutic targets and refining treatment approaches for metastatic bone disease, making it an area of research that cannot be overlooked.

2. Bone Metastases Overview

The process leading to metastatic growth of cancer in bone is regulated by a signaling interaction between the bone microenvironment and cancer cells [22, 23]. The “seed and soil” hypothesis, established by Dr. Paget [24] in 1889, posits that for optimal development, seeds need a suitable soil environment. If cancer is present, the cancer cells, referred to as “the seed”, need a suitable environment, known as “the bone microenvironment”, in order to flourish [24]. Bone is a constantly changing tissue that undergoes remodeling in response to physical and metabolic demands during an individual’s lifespan. The osteoblast, responsible for bone production, and the osteoclast, responsible for bone resorption, are the primary contributors to both bone remodeling and the development of metastases [25, 26, 27]. When tumor cells infiltrate the bone, they disrupt the usual bone remodeling process. In the case of prostate cancer, the cells promote bone formation, while in breast, lung, and renal cancer, they stimulate bone resorption [28, 29, 30, 31]. The function of the osteoclast, which is responsible for bone resorption, in the formation of bone metastases has been widely researched in recent decades. Drugs that target the osteoclast have been used to treat bone metastases and other metabolic bone diseases [32, 33, 34, 35, 36, 37, 38].

Although osteoblasts and osteoclasts are primarily involved in the formation of bone metastases, recent research has shown that many other cells residing in the bone marrow also significantly contribute to the course of the disease progression [39]. Adipocytes and osteoblasts share a common lineage originating from mesenchymal progenitor cells [40]. These progenitor cells have the potential to differentiate into either adipocytes or osteoblasts [41]. The process of adipocyte transdifferentiation into osteoblasts has been observed in both in vitro and in vivo experiments [42]. The prevalence of bone marrow adipocytes increases with age and obesity [43, 44]. Dysregulation of the osteo-adipogenic fate-determination can lead to bone diseases such as osteoporosis, accompanied by an increase in bone marrow adipose tissue. A definitive correlation has been established between the rise in bone marrow adipocytes and the occurrence of bone metastases. This was shown partly by the production of certain cytokines such as IL-6, which trigger the process of osteoclastogenesis [45, 46]. It was also published that S100A8/A9 genes, which are up-regulated in bone metastatic lung cancer cells, may be responsible for the crosstalk between lung cancer cells and bone marrow adipocytes and play a role in promoting osteolytic bone destruction in lung cancer bone metastasis [47]. There has been growing acknowledgement of the immune system’s involvement in both normal bone remodeling and bone disease. The bone marrow harbors a variety of immune cell populations, each with unique roles and functions. Cells such as Natural Killer (NK) cells, macrophages, dendritic cells, myeloid-derived suppressor cells (MDSCs) and neutrophils all contribute to the complex immune landscape of the bone marrow. These different cell populations have specialized functions that contribute to the overall defense mechanisms of the bone marrow against various immunological challenges. For example, NK cells have the ability to directly attack and eliminate cancer cells and thus represent an important line of defense against malignancies [48, 49]. Macrophages, on the other hand, have the ability to adopt different phenotypes depending on the specific context in which they are activated. They can adopt either a proinflammatory (M1) or a tumor-promoting (M2) phenotype, underlining their versatility. The M2 macrophage subtype, also known as tumor-associated macrophages (TAMs), emerges as a significant contributor to tumor progression within the bone marrow microenvironment [50, 51]. These M2 macrophages actively participate in the promotion of tumor growth, including the establishment of bone metastasis. It was demonstrated that upon arriving at the tumor site, monocytes initially differentiate into motile TAMs. These TAMs, guided by CCR2 signaling, subsequently undergo a TGFβ-mediated transformation, upregulating CXCR4, which directs them towards CXCL12-expressing perivascular fibroblasts. This migration culminates in their differentiation into sessile perivascular TAMs that facilitate tumor cell intravasation by promoting vascular leakiness. The process from monocyte recruitment to functional perivascular TAM formation is shown to be unidirectional [52].

Moreover, the bone marrow is also home to other immune cell populations, such as MDSCs and neutrophils, which play crucial roles in both immune suppression and tumor growth. MDSCs are derived from the myeloid lineage and function to suppress immune responses. They possess immunosuppressive properties that contribute to the evasion of immune surveillance by tumors [53, 54]. Additionally, neutrophils, another significant cell population within the bone marrow, also exhibit functions related to immune suppression and tumor growth. These immune cells can be influenced by various factors, including the cytokine TGFβ, which plays a pivotal role in regulating immune responses and tumor development within the bone marrow microenvironment. T cells have been shown to have a two-fold impact on the process of normal bone remodeling. They stimulate the formation of osteoclasts by means of RANKL, while simultaneously impeding osteoclast formation via the generation of interferon-gamma (INFγ) [55]. Regulatory T cells (Tregs), are abundant in cancer patients, including patients with bone metastasis, they play an essential role in immune suppression and poor prognosis Nature killer cells, which reside in the bone marrow has shown to be involved in tumor destruction properly though INFγ [56]. However, it has been seen that when these cells are eliminated, it leads to the promotion of tumor growth and the creation of metastases [57]. The anticancer efficacy of CD4+ and CD8+ T lymphocytes has been firmly established in both primary and metastatic tumors [56]. CD4+ve helper T cells are important in orchestrating immune responses in cancer and in priming and survival of CD8+ve cytotoxic T cells. Advanced ovarian cancer correlates with high number of CD8+ve cells inside the tumor tissue [58]. Given this complex interaction of various cells in the bone marrow microenvironment, it becomes clear that bone metastases are not only caused by osteoblast and osteoclast activity but also by adipocytes, immune cells, and cytokines. A full knowledge of these interactions is needed to create more effective treatment options targeting bone metastases. Bone marrow is now thought to have a role.

3. The Rationale for Targeting Growth Factor Receptors (GFRs) Pathways in Bone Metastases

Bone metastases, often arising from primary tumors such as breast, prostate, and lung cancers, pose significant clinical challenges because of their ability to disrupt normal bone homeostasis, leading to SREs [59, 60, 61]. The rationale for targeting GFR pathways in this context stems from their pivotal role in mediating tumor growth and metastatic progression. Growth factor receptors, including the EGFR, TGFβ and the FGFR, and PDGF are known to be upregulated in various cancers and are implicated in the modulation of tumor microenvironment, angiogenesis, and resistance to apoptosis.

The presence of several growth factors and their corresponding receptors on tumor cells is vital for the malignant transformation and progression. Tumor cells have the ability to generate growth factor ligands and react to these signals by expressing corresponding receptors in an autocrine fashion. Tumor epithelial cells and stromal components of the tumor may interact by producing various growth factors. Tumor cells may secrete PDGF, which stromal cells including macrophages, myofibroblasts, and fibroblasts have receptors for. Stromal cells react to PDGF by secreting IGF-1, which promotes tumor development and survival. EGFR signaling is crucial in cancer growth and epithelial to mesenchymal transition, and its function is often disrupted in epithelial malignancies. A constitutively activated IGF-IR triggers cells to undergo epithelial to mesenchymal transition within mammary gland epithelial cells. This is linked to a significant increase in cell migration and invasion [62, 63].

Specifically, in the bone microenvironment, GFR signaling influences the activity of bone-forming osteoblasts and bone-resorbing osteoclasts, the critical cells responsible for bone remodeling [64]. Dysregulation of these pathways in cancer cells and the bone microenvironment can exacerbate osteolytic and osteoblastic lesions, leading to enhanced bone destruction or abnormal bone formation. Thus, targeting GFR pathways can disrupt these deleterious interactions, curtail tumor progression, and ease SREs. Moreover, GFR-targeted therapies may synergize with treatments like bisphosphonates or RANK ligand inhibitors, offering a more comprehensive management strategy for bone metastases. The growing understanding of molecular oncology and the emergence of precision medicine, which promises more effective and less toxic therapeutic options, also fueled the pursuit of GFR pathway inhibitors. However, the development of such therapies necessitates a nuanced understanding of GFR signaling dynamics within the bone metastatic niche, alongside considerations of drug resistance and patient-specific factors.

Following the tumor’s colonization of the bone marrow, the initiation of micro-metastasis begins. During this phase, tumor cells release a variety of factors, initiating osteolysis and mobilizing factors embedded within the mineralized bone matrix [65]. This release fosters a bidirectional interaction between the tumor cells and the bone microenvironment. A critical factor in this process is TGFβ, which is liberated from the bone matrix, enhancing the proliferation of cancer cells via TGFβ receptors. Importantly, this process triggers the tumor’s production of osteolytic factors, including parathyroid hormone-related peptide (PTHrP), MMP-1, CXCR4, interleukin-11, and connective tissue growth factor (CTGF), Fig. 1. This complex interplay between tumor cells and the bone microenvironment is pivotal in cancer progression and the development of metastasis [66, 67].

Fig. 1.

This figure illustrates the intricate interaction between growth factors and the bone microenvironment in the context of bone metastases. It highlights the pivotal roles of transforming growth factor-β (TGFβ) and hepatocyte growth factor (HGF), Epidermal growth factor (EGF) in promoting bone metastatic growth. TGFβ, released during bone destruction, and HGF, regulated by molecular mechanisms, synergistically facilitate the colonization and proliferation of cancer cells within the bone matrix. This dynamic interplay not only underscores the complexity of cellular signaling in the bone microenvironment but also elucidates potential therapeutic targets for disrupting these pathways and inhibiting the progression of bone metastases. IL-6, Interleukin 6; VEGF, vascular endothelial growth factor; FGFs, fibroblast growth factors; MMPs, matrix metalloproteinases; PTHrP, parathyroid hormone-related peptide.

Exosomes, which are extracellular vesicles produced by all cells, play crucial roles in the development and progression of cancer. They are involved in several aspects of tumor development including tumor initiation, immune suppression, immune surveillance, metabolic reprogramming, angiogenesis, and the polarization of macrophages [68]. Exosomes can carry different types of biomolecules, including growth factors, which contribute to intercellular communication and the alteration of recipient cell behavior [69]. These exosomal contents can be transferred into recipient cells, leading to changes in cellular interactions [70]. Exosomes also have the ability to modulate components of the tumor microenvironment and influence the proliferation and migration rates of cancer cells. Additionally, exosomes can enhance or reduce cancer cell response to various types of cancer therapy including radiation therapy and chemotherapy and can trigger chronic inflammation and immune evasion [71].

Exosomes carry “cargo” and are internalized by endothelial cells to induce angiogenesis. It was published that exosomes derived from ovarian cancer cells affect VEGF expression in endothelial cells. It was found that these exosomes enhance VEGF expression and secretion in endothelial cells, potentially promoting angiogenesis. The study highlights the role of cancer cell-derived exosomes in modifying the tumor microenvironment to favor cancer progression [72]. A recent study provided new insights into the role of exosomes in cancer biology, particularly in the context of tumor dormancy and the microenvironment’s role in cancer progression. This study showed that exosomal ITGB6 from dormant lung adenocarcinoma cells activates cancer-associated fibroblasts (CAFs) through a KLF10 positive feedback loop and the TGFβ pathway, highlighting a mechanism by which dormant cancer cells may contribute to tumor recurrence and progression [73]. Therefore, exosomes and their cargo, including growth factors, have significant implications for the development and progression of cancer.

4. Growth Factor Receptors and Their Role in Bone Metastases
4.1 Role of Fgfr in Cancer and Bone Metastases

The Fibroblast Growth Factor Receptor (FGFR) family represents a pivotal group of cell surface receptors crucial for regulating cell proliferation, differentiation, and survival. The history of FGFR discovery traces back to the late 1970s and early 1980s when the groundbreaking work of researchers like Michael Stoker and George Todaro identified a family of proteins called fibroblast growth factors (FGFs) that stimulated cell growth in fibroblast cultures. Following this discovery, efforts were made to elucidate the receptors through which FGFs exert their effects. In 1988, Jaye et al. [74] identified the first member of the FGFR family, FGFR1, using a combination of molecular cloning techniques. Subsequent research led to the identification of additional FGFR family members, including FGFR2, FGFR3, and FGFR4 [75]. The discovery of FGFRs has led to several novel findings and insights into cellular signaling mechanisms. One significant discovery involves the diverse roles of FGFRs in various cellular processes beyond traditional cell growth and differentiation [76]. For instance, FGFR signaling has been implicated in cell migration, angiogenesis, tissue repair, and organogenesis, highlighting the multifaceted nature of FGFR-mediated signaling pathways. Additionally, the identification of FGFR mutations in various cancers has provided critical insights into the role of aberrant FGFR signaling in tumorigenesis [77, 78]. Furthermore, recent studies have uncovered intricate crosstalk between FGFR signaling and other signaling pathways, such as the MAPK and PI3K/Akt pathways, elucidating complex regulatory networks that govern cellular behavior and fate [79, 80].

A high level of diversity characterizes the FGF family, with 22 ligands found in mammals. These ligands are grouped into six subfamilies based on their sequence homology and phylogenetic relationships. There are five paracrine subfamilies and one endocrine subfamily included in this classification [75].

Fibroblast Growth Factor (FGF) and Fibroblast Growth Factor Receptor (FGFR) Signaling is crucial in the process of bone formation and maintaining a stable internal environment [81]. Both FGFR1 and FGFR2 activating mutations enhance osteoblast differentiation [82]. Conversely, FGFR3 is recognized as an inhibitory factor in bone development [83]. FGF8 was shown to impact osteoblast differentiation in laboratory settings by influencing the differentiation of bone marrow mesenchymal cells into osteoblasts and promoting bone formation [84]. Disruption of these signaling pathways may lead to various illnesses. Specific skeletal defects in humans are associated with mutations in FGFR. The presence of FGFR2 mutations in humans is linked to craniosynostosis, bent bone dysplasia, and other skeletal diseases, suggesting its involvement in bone formation [85, 86]. In a more recent study by Shin et al. [87] they showed that in a mouse model of Fgfr 2S252W/+ mutant osteoblasts, abnormally increased RANKL expression caused an imbalance between osteoblast and osteoclast activity and net bone loss and short limbs in this model.

FGF plays a pivotal role in bone metastases. Several FGF ligands have been reported to be involved in prostate cancer tumor initiation and progression. FGF1, FGF2, FGF6, FGF8, FGF19, and FGF23 have been reported to be involved in prostate cancer tumor initiation and progression [88, 89, 90]. TME-secreted FGFs play a crucial role in tumorigenesis and tumor resistance to therapy. In estrogen receptor-positive (ER+ve) breast cancer, the tumor microenvironment secretes FGF2, which is considered a major factor and has been identified as a significant factor in promoting drug resistance to anti-estrogens, mTORC1 inhibitors, and phosphatidylinositol 3-kinase inhibitors. This resistance, which was linked to FGF2 signaling and mediated by ERK1/2 activation affecting Cyclin D1 and Bim, was reversed by targeting FGF2 or FGF receptors [91]. When ER+ve breast cancer cells were cultured in fibroblast-derived extracellular matrix (ECM) scaffolds, it exhibits increased ER signaling via a mechanism dependent on the MAPK pathway and independent of estrogen. This enhanced signaling is attributed to the ECM acting as a reservoir for FGF2, which binds to the ECM and promotes ER signaling. As a result, cells in the ECM environment show reduced sensitivity to ER-targeted therapies, a challenge that can be countered by inhibiting the FGF2-FGFR1 interaction [92].

In a study using 25 patient bone metastases sample, immunohistochemical analysis showed that 76% of these samples expressed FGF-8. In PC-3 prostate cancer cells, FGF-8 expression led to increased growth of intratibial tumors in mouse model and the formation of both osteolytic and osteoblastic lesions. These data suggest that FGF-8 plays a major role in modulating the interactions between prostate cancer cells and the bone microenvironment, thus contributing to the development of bone metastasis [93, 94]. FGF23 is extensively expressed in osteocytes, which are the most abundant bone cells. Mansinho et al. [95], reported from a study that involved 122 patients with types of solid tumor and bone metastases treated with bone-targeted agents, that lower baseline levels of serum FGF23 are associated with longer overall survival and time to skeletal-related events (SREs). The findings suggest the potential of FGF23 as a prognostic biomarker for bone metastases and warrant further research into drugs targeting the FGF signaling pathway [95]. When MDA-MB-231 breast cancer cell line cultured in vitro or injected into mammary glands (without bone metastasis) exhibited weak FGF23 immunoreactivity. On the other hand, these cells showed intense FGF23 immunoreactivity when metastasized in the long bones of nu/nu mice, indicating that these cells synthesize FGF23 in a bone metastatic environment [96].

The importance of FGFR1 in bone metastases was highlighted recently by Labanca et al. [97]. This group showed that different isoforms of FGFR1 are expressed in various PCa subtypes. They reported that in an Intracardiac mouse model of bone metastases, injection of FGFR1-expressing PC3 cells led to reduced survival and an increased incidence of bone metastases. Furthermore, immunohistochemical studies on human castration-resistant prostate cancer (CRPC) bone metastases showed significant enrichment of FGFR1 expression compared to nonmetastatic primary tumors. The study also identified an increase in the expression of ladinin 1 (LAD1), an anchoring filament protein, in FGFR1-expressing PC3 cells, which was also enriched in human CRPC bone metastases. This study highlights the novel finding that FGFR1 expression in PCa cells enhances metastatic behavior [97].

4.2 Role of EGF/EGFR in Cancer and Bone Metastases

The history of the EGF and its receptor (EGFR) is marked by groundbreaking discoveries that have significantly advanced our understanding of cellular signaling and cancer biology. The story began in the late 1950s when Stanley Cohen and Rita Levi-Montalcini [98] identified a substance in mouse salivary glands that stimulated epidermal growth. This substance was later characterized as EGF, a potent mitogen capable of promoting cell proliferation and differentiation [98]. Subsequent research efforts led to the purification and sequencing of EGF, unraveling its role as a key regulator of epithelial cell growth and development. In the early 1980s, the discovery of EGFR, the receptor through which EGF exerts its effects, revolutionized our understanding of signal transduction mechanisms [99]. Michael Waterfield [100] and Antony Ullrich [101] independently identified and characterized EGFR, revealing its role as a tyrosine kinase receptor involved in mediating cellular responses to EGF and other ligands. The elucidation of the EGF-EGFR signaling pathway paved the way for numerous groundbreaking discoveries, including the identification of EGFR mutations in various cancers and the development of targeted therapies such as EGFR inhibitors [102, 103]. Moreover, recent research has unveiled novel mechanisms underlying EGFR signaling, including receptor dimerization, endocytosis, and downstream signaling cascades, providing new insights into the complexity of EGFR-mediated cellular responses and offering potential avenues for therapeutic intervention in cancer and other diseases.

The EGFR, sometimes referred to as erbB1 or HER1, is a constituent of the EGFR receptor family, which encompasses HER2/neu (erbB2), HER3 (erbB3), and HER4 (erbB4). EGFR functions as a receptor tyrosine kinase [104, 105]. Once the ligand binds to its receptor, the receptor is dimerized, and its cytoplasmic tails get phosphorylated, and activating several cellular signaling pathways, including the MAPK pathway, the phosphoinositide 3-kinase (PI3K)-AKT pathway, and the STAT pathway. This pathway activation can lead to an increase in cell proliferation, migration, and survival [106]. In non-small cell lung cancer (NSCLC) mutations of the EGFR genes is considered a major driver of the disease [107, 108]. Pancreatic ductal adenocarcinoma (PDAC) has a high incidence rate and a poor prognosis because of late diagnosis and the absence of effective therapy [109]. Overexpression of the EGFR is commonly associated with pancreatic cancer progression, but its correlation with survival rates remains unclear [109, 110]. Although it is shown that EGFR plays an important role in the pathogenesis of pancreatic ductal carcinoma, its overexpression is associated with poor prognosis. On the other hand, EGFR somatic mutations are not typically common in pancreatic cancer and EGFR mutations in pancreatobiliary tumors are primarily loss-of-function mutations and are not responsive to anti-EGFR treatment [111].

Several EGFR-targeting agents for the treatment of various human cancer types have been in clinical development. This includes anti-EGFR monoclonal antibodies such as cetuximab and panitumumab and reversible EGFR tyrosine kinase inhibitors such as gefitinib and erlotinib. Some have been approved to treat several types of cancer [112, 113, 114]. In a study analyzing data from 295,213 patients with invasive breast cancer covering the period from 2010 to 2014, it was found that at diagnosis, bone metastases occurred in 3.28% of newly diagnosed breast cancers. This was the highest incidence rate among the studied metastatic sites, which also included lung (1.52%), liver (1.20%), and brain (0.35%) metastases. The HR+/HER2- subtype was associated with an elevated risk of bone metastases compared to HR+/HER2+. The triple-negative subtype (HR-/HER2-) was associated with a significantly lower risk of bone metastases compared to HR+/HER2- tumors [115].

A study aimed to determine the prevalence of ERBB2/HER2 mutations in bone metastases of breast cancer and the associated phenotypes. A total of 231 breast cancer patients with bone metastases were analyzed. It was found that 7 out of 231 patients (approximately 3%) with bone metastases had gain-of-function mutations in the ERBB2/HER2 gene. All reported cases with the HER2 mutation were HER2-ve based on conventional testing for protein expression and gene amplification, indicating a potential oversight in identifying candidates for specific anti-HER2 therapies [116].

EGFR mutations are presently utilized as predictive markers of clinical response to EGFR-tyrosine kinase inhibitors (TKIs); these mutations can cause amplification and overexpression of the EGFR protein and other carcinogenic mechanisms of EGFR tyrosine kinase activity abnormality [117]. Mutations in EGFR and kRAS genes are linked to overall survival in NSCLC patients with symptomatic bone metastases. In 139 patients with NSCLC treated for symptomatic bone metastases between 2007 and 2014, with known mutation statuses, it was reported that patients with EGFR mutations, comprising 15% of the study population, had a significantly longer median OS of 17.3 months. In contrast, patients with kRAS mutations, making up 34% of the study population, had a much shorter median OS of only 1.8 months. Compared with patients who were EGFR-positive, those who were EGFR-negative had a 2.5 times higher risk of death. This data highlights the significant impact of EGFR and kRAS mutations on the overall survival of NSCLC patients with symptomatic bone metastases [118].

In metastatic castration resistant prostate cancer (mCRPC) patients who had failed androgen-deprivation therapy and received docetaxel chemotherapy, circulating tumor cells (CTCs) were enumerated and EGFR expression was also assessed. Among patients with five or more CTCs, 40.5% (15/37) were found to have EGFR-positive CTCs. Patients with EGFR-positive CTCs had a notably shorter overall survival of 5.5 months compared to 20.0 months in those with EGFR-negative CTCs. The study concluded that EGFR expression in CTCs is a crucial factor in assessing response to chemotherapy and predicting disease outcome [119].

The receptor activator of Nuclear Factor κB RANK/RANKL/OPG pathway is important in the development of bone metastases [120]. Epidermal growth factor receptor signaling plays an important role in bone remodeling and development. EGFR is known to promote osteoclast formation and activation and mice deficient in EGFR receptor display severe bone phenotype and growth retardation [121, 122]. In a multicenter study including patients with EGFR mutated EGFR+, KRAS+ and EGFR/KRAS wildtype metastatic NSCLC, were 63% of the patients had bone metastases at diagnosis or developed bone metastases during the disease course. No association existed between EGFR expression and the presence of bone metastases. RANKL expression and RANKL/OPG ratio were significantly higher in patients with bone metastases compared to patients with no metastases [123].

When EGFR mutations were compared between primary lung adenocarcinoma tumors and corresponding bone metastases, EGFR mutations were found in 61 primary tumors (53.04%) and 67 corresponding metastases (58.26%). The consistency of EGFR mutations between matched BMs and primary tumor samples was 80.87%, while the disparity was 19.13% suggesting that both primary tumor and metastatic sites should be considered for EGFR mutation testing to guide treatment decisions effectively [124].

4.3 Role of TGFβ/TGFβR in Cancer and Bone Metastases

The history of TGFβ and its receptors is characterized by significant milestones in the understanding of cellular signaling and developmental biology. In the early 1980s, the groundbreaking work of Michael Sporn, Anita Roberts, and others led to the identification and purification of TGFβ, a multifunctional cytokine with diverse roles in cell proliferation, differentiation, immune regulation, and tissue homeostasis [125, 126]. Subsequent research efforts uncovered a family of TGFβ isoforms, including TGFβ1, TGFβ2, and TGFβ3, each encoded by distinct genes but sharing structural and functional similarities. Concurrently, the discovery of TG-β receptors expanded our understanding of TGFβ signaling mechanisms. In the late 1980s and early 1990s, researchers such as Joan Massagué [127] and Bert Vogelstein identified and characterized two types of TGFβ receptors, known as type I (TβRI) and type II (TβRII) receptors, which mediate the cellular responses to TGFβ ligands. Further studies elucidated the intricate signaling pathways activated by TGFβ receptors, including the canonical Smad-dependent pathway and non-Smad signaling cascades involving MAPKs, PI3K/Akt, and Rho GTPases [128, 129]. Moreover, recent advances in our understanding of TGFβ signaling have revealed its critical roles in embryonic development, wound healing, immune regulation, and cancer progression. Novel discoveries include the identification of TGFβ receptor mutations in human diseases and the intricate cross-talk between TGFβ signaling and other signaling pathways, offering new insights into the complex regulatory networks governing cellular behavior and tissue homeostasis.

The multifunctional cytokine known as Transforming Growth Factor-β (TGFβ) is essential for several cellular functions, such as proliferation, differentiation, cell death, and immune system control [130, 131]. Cancer, cardiovascular diseases, fibrosis, and several other disease disorders have been associated with the dysregulation of TGFβ functions [131, 132, 133, 134, 135]. Curiously, its function in cancer is multifaceted and perplexing. By increasing apoptosis, promoting cell cycle arrest, and reducing proliferation in the early phases of tumor growth, TGFβ functions as a tumor suppressor. This is because it can regulate the cell cycle and trigger mechanisms that stop the unchecked proliferation of cells, which is a characteristic of cancer. But TGFβ’s function changes, and it becomes a promoter of tumor growth and metastasis, as cancer advances [134, 135, 136, 137, 138]. Part of this could be because most of the tumor cells and tumor microenvironment respond some way or another to TGFβ in a context dependent way, which makes the interpretation of experimental result difficult to predict [139]. The “TGFβ paradox” describes this occurrence in cancer.

In many cases, tumor cells find ways to circumvent TGFβ’s tumor-suppressing effects as cancer progresses. They start taking advantage of the TGFβ signaling pathway to increase their numbers, become larger and more resilient to TGFβ mediated induction of the proapoptotic BMF. It is suggested that caveolin 1 (CAV1) is protecting hepatocellular carcinoma cells (HCC) cells from TGFβ-induced apoptosis, causing an increase in HCC growth and migration [140]. Reasons for this include modifications to tumor cell signaling pathways and changes to the tumor microenvironment. When cancer has progressed to an advanced stage, TGFβ can encourage the process of epithelial-to-mesenchymal transition (EMT), whereby cells in the epithelium take on the invasive and migratory characteristics of mesenchymal cells. Through Smad signaling pathway, TGFβ controls the expression of the master transcription factors Snail1/2, ZEB1/2, and Twist [141]. This change is essential for cancer to progress and metastasis to other parts of the body [142].

TGFβ signaling pathway is crucial for bone metastasis growth. Numerous studies demonstrate that TGFβ’s activity and utility are both complicated and context-dependent. In MDA-231 breast cancer cells, a reporter gene was expressed using a retroviral vector with a TGFβ-sensitive promoter in an animal model of breast cancer bone metastases. The work showed that the reporter detected TGFβ-Smad signaling in bone and that reducing Smad4 expression in breast cancer cells inhibited bone metastasis development [67]. The TGFβ-Smad signaling pathway initiates PTHrP production, which is widely expressed in diverse tissues and has a similar sequence to PTH. The majority of breast cancer and bone metastases express PTHrP, which contributes to osteolytic lesions and humoral hypercalcemia. Prospective research found that primary breast cancer patients with PTHrP expression had fewer bone metastases [143, 144]. This finding may explain the rise in PTHrP expression in breast cancer bone metastases. Following bone resorption, TGFβ is released from the mineralized bone matrix, rather than PTHrP expression being amplified in tumor cells colonizing the bone. In MDA-231 breast cancer cells, blocking TGFβ signaling by stable transfection of DNTRII led to reduced PTHrP synthesis. This inhibition prevented osteolytic lesions [145]. Persistent overexpression of dominant-negative Smad 2, 3, and 4 inhibited PTHrP synthesis in MDA-231 breast cancer cells. This turned off RANKL production. This prevented increased RANKL synthesis, which promotes osteoclast development and metastasis. This prevented enhanced RANKL synthesis, which promotes osteoclast development and metastasis [144, 146].

A complicated interplay between TGFβ and Wnt signaling promotes effective colonization, dormancy, and outgrowth during bone metastases. Wnt suppression by DKK1 is crucial for immune evasion by quiescent micro-metastases and late-stage osteoclastogenesis, whereas TGFβ signal maintains DTC quiescence in bone [147]. Wnt signaling from DTCs’ interaction with bone vascular E-selectin promotes metastatic colonization. Recent research by Esposito et al. [148] found that TGFβ causes DACT1 protein condenses in the cytoplasm, which suppress Wnt signaling and persist in vivo. The research also found that breast and prostate cancer bone metastases need DACT1. This study reveals the complex relationship between TGFβ and Wnt signaling pathways in bone metastases, suggesting tailored cancer therapeutic strategies [148].

4.4 Role of VEGF/VEGFR in Cancer and Bone Metastases

The history of VEGF and its receptors represents a cornerstone in our understanding of angiogenesis and vascular biology. In the late 1980s and early 1990s, pioneering work by researchers including Napoleone Ferrara [149] and Harold Dvorak [150] led to the identification and characterization of VEGF as a potent angiogenic factor. This discovery revolutionized our understanding of how new blood vessels form and grow [151, 152]. Subsequent research efforts focused on unraveling the molecular mechanisms underlying VEGF signaling, leading to the identification of several VEGF receptor isoforms, notably VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3. These receptors, primarily expressed on endothelial cells, mediate the biological effects of VEGF through intricate signaling pathways [153]. Novel discoveries in recent years have elucidated additional roles of VEGF and its receptors in various physiological and pathological processes, including lymphangiogenesis, vascular permeability, and tissue repair. Moreover, the identification of VEGF receptor mutations and alternative splicing variants in diseases such as cancer has opened new avenues for targeted therapies aimed at disrupting pathological angiogenesis [154, 155].

Since the isolation of VEGF and its identification as a potent mitogen for endothelial cells, VEGF has been proven to be crucial in vasculogenesis during embryonic development and angiogenesis in embryonic, postnatal, and adult instances like wound healing and female reproductive cycles [156, 157]. VEGF’s primary receptors are VEGFR-1 (Flt-1) and VEGFR-2 (KDR) [158, 159]. VEGFR-2 has greater signaling activity than VEGFR-1 and is the main mediator of VEGF’s mitogenic effects, despite a lower binding affinity [158]. Elevated levels of Vascular Endothelial Growth Factor (VEGF) have been observed in a range of tumors, both benign and malignant. This includes various cancer types, such as melanoma, kidney cancer, breast cancer, lung cancer and others [160, 161].

Tumor neovascularization is critical for their proliferation and sustenance. VEGF is a major tumor proangiogenic factor that is upregulated during tumor growth [162, 163]. Hypoxia is a potent stimulator of VEGF expression. Hypoxia-inducible factor-1 or HIF-1 is known to be the regulate over 60 downstream genes, including vascular endothelial growth factor (VEGF) [164]. High levels of HIF-1α and VEGF are implicated both in small cell (SCLC) and non-small-cell lung cancer (NSCLC). Measuring serum and pleural effusion HIF-1α level revealed an increase in serum and pleural effusion level of HIF-1α level in lung cancer patients compared to patients with benign lung disease No difference in the VEGF level in the serum or pleural effusion between patients with lung cancer and benign lung disease [165]. In response to hypoxia, both HIF-1α and VEGF-A were upregulated in lung cancer cells. When lung cancer cells were treated with anti-HIF-1α siRNA prior to hypoxia exposure, it reduced both HIF-1α and VEGF-A expressions. These data suggested that the production of HIF-1α led to an increase in the expression of VEGF-A, and the activation of the HIF-1α/VEGF pathway was responsible for the hypoxia-induced angiogenesis [166].

Biopsy samples from patients with SCLC were examined using IHC, a significant correlation between HIF-1α nuclear staining and VEGF staining was observed. A positive correlation between VEGF and VEGF-R2 expression was also observed in the same samples, suggesting suggesting a possible VEGF/VEGFR-2 autocrine pathway in SCLC [167]. It was demonstrated that in cervical cancer patients who had a bulky tumor, pelvic lymph node involvement, or parametrial infiltration, the levels of VEGF-A were significantly higher compared to patients who did not have these factors. Furthermore, it was found that both VEGF-A and VEGFR-2 predict significantly worse overall survival, and that serum levels of VEGF-A and VEGFR-2 are independent prognostic factors in patients with cervical cancer in terms of overall survival [168]. VEGF, MMP-9, and cancer antigen (CA) 15-3, plasma levels in patients with breast cancer were significantly higher when compared with healthy women [169].

In an in vitro experiment using conditioned medium from a prostate cancer cell line (C4-2B), which is rich in VEGF, showed the induction of osteoblast differentiation as well as the production alkaline phosphatase and osteocalcin which are bone formation markers. They found that the use of VEGFR tyrosine kinase inhibitor PTK787 blocked these osteoblastic activities induced by the conditioned medium and reduced the bone lesion in prostate cancer mouse model suggesting the important role of VEGF in prostate cancer bone metastases [170]. When renal cell carcinoma cell line (RCC-Luc) was compared to breast and prostate tumor cell lines, it was found that vegf-a expression is 10-fold more in RCC cells. When tested in vivo, it was shown that the bone metastatic nature of this cell line is independent of tumor vascularity [171]. The most important findings on the role of growth factors in bone metastases are summarized in Table 1.

Table 1.A brief overview of growth factor receptors’ intricate functions in cancer progression and bone metastases.
Growth Factor Receptor Role in Cancer and Bone Metastases Key Findings
FGFR Crucial for cell proliferation, differentiation, and survival. FGFR mutations in various cancers indicate aberrant signaling in tumorigenesis. FGFR1 and FGFR2 mutations enhance osteoblast differentiation, whereas FGFR3 inhibits bone development. FGF ligands, notably FGF1, FGF2, FGF6, FGF8, FGF19, and FGF23, play roles in tumor initiation and progression in prostate cancer and drug resistance in ER+ve breast cancer. FGF8 and FGF23 specifically implicated in bone metastases.
EGFR Key regulator of epithelial cell growth. EGFR mutations associated with various cancers and targeted therapies. EGFR overexpression is linked with pancreatic cancer progression and poor prognosis. EGFR mutations serve as predictive markers for clinical response. EGFR-positive CTCs in mCRPC associated with shorter survival. EGFR signaling promotes osteoclast formation and is important in bone remodeling.
TGFβR TGFβ signaling plays dual roles as tumor suppressor and promoter. TGFβ signaling pathway is crucial for bone metastasis growth. TGFβ’s role shifts from tumor-suppressing to promoting tumor growth and metastasis as cancer progresses. It controls EMT and initiates PTHrP production, contributing to osteolytic lesions and bone metastases. Interplay between TGFβ and Wnt signaling affects colonization, dormancy, and outgrowth in bone metastases.
VEGFR Critical for angiogenesis and vascular biology. VEGF and its receptors play roles in various physiological and pathological processes. VEGF signaling is crucial for tumor neovascularization and sustenance. High levels of HIF-1α and VEGF implicated in lung cancer. VEGF promotes osteoblast differentiation and bone formation markers, indicating its role in bone metastases.

FGFR, Fibroblast Growth Factor Receptor; EGFR, Epidermal Growth Factor Receptor; TGFβR, Transforming Growth Factor-β Receptor; VEGFR, Vascular Endothelial Growth Factor Receptor; FGF, fibroblast growth factor; CTCs, Circulating tumor cells; mCRPC, metastatic castration resistant prostate cancer; TGFβ, Transforming Growth Factor-β; EMT, epithelial-to-mesenchymal transition.

5. Therapeutic Strategies: Targeting Growth Factor Receptor (GFRs) in Bone Metastases
5.1 Targeting FGF/FGFR

AZD4547 is a specific inhibitor of the FGFR1, 2, and 3 tyrosine kinases. AZD4547 effectively decreased the activity of recombinant FGFR kinase in laboratory conditions and inhibited FGFR signaling and proliferation in tumor cell lines that exhibited an abnormal expression of FGFR [172]. The efficacy of the selective FGFR inhibitor, AZD4547, has been studied in the bone microenvironment. In an orthotopic breast cancer bone metastasis mouse model, AZD4547 suppressed osteoclastogenesis and tumor-induced osteolysis, indicating its potential to suppress both tumor and stromal components of bone metastasis​. This data suggests that AZD4547 can be a potential therapeutic agent for metastatic bone disease in breast cancer [19]. AZD4547 was tested in a PDX model of pancreatic cancer bone metastases. Before drug testing, the PDX model of pancreatic cancer bone metastases showed significant FGFR1 expression. AZD4547 reduced growth better than capecitabine, a chemotherapeutic medication. The two synergistically increased total growth inhibition (TGI) by 70.5%. In addition, AZD4547 reduced tumor cell proliferation and FGFR1 targets like p-Akt expression [173]. The researchers did not explain AZD4547’s mechanism of action, and more studies are necessary to establish this mechanism.

5.2 Targeting EGF/EGFR

Over the last two decades, two primary targeted therapeutics have been discovered to inhibit HER-driven pathways: small molecule drugs that reduce intracellular tyrosine kinase activity and mAbs that target the extracellular domain (ECD) of the receptors. While targeted treatment has made great progress, there is still a strong need for novel therapies for HER-positive tumors. Targeted therapy using TKIs or mAbs alone may be ineffective owing to limited cytotoxicity to cancer cells as well as and poor tumor penetrance [174].

The majority of studies focused on EGFR gene alterations specifically in primary lung cancer. There is less information known about the prevalence of these genetic alterations in metastatic adenocarcinoma tumors and their impact on the effectiveness of EGFR TKIs treatment in such instances. The presence of genetic abnormalities in the cells of the primary tumor makes it highly likely that these abnormalities will also be found in the metastases [175]. The relationship between the presence of EGFR gene mutations and the occurrence of metastases, as well as their organ location, remains unknown [176, 177]. A retrospective study was conducted to investigate the relationship between patients NSCLC with bone metastases harboring and EGFR mutations and the therapeutic efficacy of EGFR-TKIs. A total of 604 patients were enrolled in the study, unfavorable progress free survival and overall survival were observed in the bone metastases versus non metastatic group [178].

In a mouse model of intratibial human NSCLC cell line H1975 bone metastases, Osimertinib alone showed a better effect on bone metastases pathology compared to Osimertinib + bevacizumab or vehicle treated mice [179]. The study demonstrates that osimertinib, both alone and in combination with BV, is effective in regressing bone metastases from EGFR-mutant lung adenocarcinoma in a mouse model, suggesting its potential as a clinical treatment option for NSCLC patients with bone metastasis. A case report of patient with lung cancer and solitary bone metastases received osimertinib monotherapy for 12 month shows the bone metastasis to have no viable cancer cells upon pathological examination [180]. In a more recent study by Brouns et al. [181], the examination of patients with EGFR-mutated NSCLC who were subjected to osimertinib treatment revealed a notable observation. It was shown that at the initiation of treatment, approximately 51% of patients exhibited bone metastases. Subsequently, during the median follow-up period of 23.4 months, it was observed that 10% of patients developed new bone metastases or experienced progression of SRE, while 39% of patients encountered at least one skeletal-related event (SRE). The median overall survival (OS) subsequent to the occurrence of bone metastasis was found to improve. These findings serve to emphasize the noteworthy prevalence of bone metastases and SREs both before and during osimertinib treatment. Consequently, these findings advocate for the adoption of bone-targeted agents in this particular patient cohort, as well as the incorporation of bone-specific endpoints in clinical trials [181].

Bisphosphonates (PBs) are class of antiresorptive drugs that are commonly used in patients with bone metastases. Bisphosphonates decrease the occurrence of skeletal-related events (SREs). The data available on the use of such bisphosphonates to treat lung cancer patients with these agents are scarce [182]. Testing was done to evaluate the combined effect of bisphosphonates and EGFR-TKIs in treating NSCLC with bone metastases. The study found that bisphosphonates combined with EGFR-TKIs led to a statistically significant longer progression-free survival (PFS) compared to EGFR-TKIs treatment alone and that patients without SREs had significantly better overall survival (OS) [183].

Correctly assessing the bone lesion is crucial for patients with non-Small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Mutation. In a cohort of 45 patients treated with Osimertinib, despite the fact that some of these patients developed osteoblastic bone reaction (OBR) as accessed by x-ray, but also showed a trend toward longer skeletal related events-free survival (SRE-FS) than the non-OBR group [184]. This observation highlights that, in patients with EGFR-mutant NSCLC treated with Osimertinib, OBR should not be mistaken for disease progression.

5.3 Targeting TGFβ/ TGFβR

The mineralized bone matrix is the largest store of TGFβ in the body. Upon bone destruction by tumor stimulated osteoclasts, TGFβ will be released. TGFβ has the ability to promote and exacerbate bone metastases by the induction of specific genes [144, 185]. A small molecule inhibitors that inhibits the TGFβ receptor kinase catalytic activity of TRI/ALK5 via ATP-competitive inhibition has been used to target TGFβ pathways in bone metastases. We and others have reported that the use of selective TGFβ receptor I kinase inhibitor reduced bone metastases in various types of cancer including breast, prostate, and melanoma [17, 61]. Neutralizing antibodies against TGFβ may decrease the level of active TGFβ signaling. Using neutralizing antibodies against TGFβ is another strategy to target TGFβ and its receptors. Pan-neutralizing antibodies have been used to target both individual ligands and all three isomers of TGFβ. Specific inhibition of TGFβ1 seems to provide anticancer benefits without the cardiovascular damage linked to inhibiting TGFβ2 or TGFβ3. Using 1D11 TGFβ neutralizing antibody reduced bone metastases burden in the animal model of breast cancer bone metastases [18]. We previously published the use of natural product Halofuginone (HF) to treat bone metastases in the mouse model. Halofuginone is derivative, originally isolated from the Chinese plant Dichroa febrifuga. Halofuginone inhibited TGFβ signaling in vitro in the cell line from multiple tumor types. We conducted an experiment using mice to study the spread of breast and prostate cancer to the bones. Our findings revealed that HF therapy dramatically decreased bone damage in both of these cancer models [61]. Although HF therapy showed the ability to block the transmission of TGFβ signals in bone metastases, however the exact method by which it works is yet not understood. Inhibiting TGFβ signaling in combination with a variety of cytotoxic agents can improve the therapeutic efficacy in patients with bone metastases. An in vitro experiment demonstrated that there is a correlation between the presence of serum and the capacity of rapamycin to cause G1 arrest, and that TGFβ is sufficient to decrease rapamycin-induced apoptosis in MDA-MB231 breast cancer cells [186].

5.4 Targeting VEGF/VEGFR

β2AR stimulation in osteoblasts induced proangiogenic effect. This effect was shown to be mediated by VEGFA in a mouse model of breast cancer bone metastases, using an antibody that specifically breaks VEGFA/VEGFR2 signaling pathway (mcr84) showed a significant reduction in bone metastatic lesion vs control treated mice [187]. TAS-115 is a tyrosine kinase inhibitor that blocks both VEGFR, and hepatocyte growth factor MET signaling pathway. When used an ex-vivo bone organ culture, it inhibited the osteolytic effects of PC3 prostate cancer cells on calvarial bone. A similar effect was reported by inhibiting bone destruction in an intraosseous model of prostate cancer suggesting that tyrosine kinase signaling in host pre-osteoclasts/osteoclasts is crucial for tumor cell-induced bone destruction, and targeting MET/VEGF receptor/FMS activity makes it a prospective therapeutic choice for bone metastases in prostate cancer patients [188]. Similarly, a combination of the VEGFR inhibitor (axitinib) and the c-MET inhibitor (crizotinib) inhibited the bone metastases lesion size in a castration-resistant prostate cancer animal model [189]. Cabozantinb is an orally bioavailable inhibitor of pro-oncogenic tyrosine kinases, including MET, vascular endothelial growth factor receptors (VEGFRs), and AXL that is orally bioavailable [190]. A subgroup analysis of the phase III METEOR trial when patient with renal cell carcinoma with bone metastases received cabozantinb there was a significant improvement in progress free survival (PFS), overall survival objective response rate (ORR) when compared with everolimus [191]. This is in contrast to the study by Smith et al. [192], where they found that cabozantinib did not have a significant improvement in overall survival (OS) in patients with metastatic castrate-resistant prostate cancer (mCRPC) compared to patient receiving prednisone. Improvement in bone markers was reported with cabozantinib in this study [192]. Patient with renal cell carcinoma treated with combined VEGF-targeted therapy, pazopanib 800 mg orally once daily, or sorafenib 400 mg orally twice daily and radium 223 shows tolerability to the treatment regimen [193].

Both preclinical and clinical investigations, including those focused on zoledronic acid (ZA), a class of bisphosphonates, have demonstrated that the combination of BPs and targeted systemic cancer treatments can potentially impact the prognosis of individuals with metastatic bone cancers [194]. Although tyrosine kinase inhibitors (TKIs) and bevacizumab have proven to be effective in treating individuals with metastatic clear cell renal cell carcinoma (m-ccRCC), their effectiveness seems to be reduced when used to treat patients with bone metastases [195]. In order to deliver optimal care to patients with bone metastatic clear cell renal cell carcinoma (m-ccRCC), a common approach is to administer a combination of tyrosine kinase inhibitors (TKIs) and bisphosphonates (BPs), with a specific focus on zoledronic acid (ZA). When administered together, TKIs and bisphosphonates can exert a stronger impact on the amount of VEGF and other potential anticancer activities. Combining these two drugs can enhance the effectiveness of the treatment, but it can also raise its toxicity [196].

6. Challenges in Targeting GFRs

Growth factor receptors, such as TGFβ, EGFR, VEGFR, and others, play a crucial role in the advancement of cancer and the formation of metastasis, as previously mentioned. Receptor-targeting inhibitors are used in the treatment of cancer (Table 2, Ref. [17, 18, 19, 61, 144, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 185, 187, 188, 189, 190, 191, 192, 193]). Nevertheless, the development of medication resistance often occurs, hence diminishing the efficacy of these therapies. The resilience of these rugs may be linked to several processes, including genetic mutations, epigenetic modifications, and activation of alternate pathways. The intricacies of medication resistance were well shown by a multiscale modeling approach to study drug resistance in glioblastoma [197]. The complexity of the relationship is due to the variety in the bone microenvironment and the heterogeneity of tumor cells. Focusing on creating medicines that target both the tumor cells and the bone microenvironment is crucial. As previously mentioned, several of the current combination medicines specifically target both the tumor itself and its surrounding environment [194, 196]. The animal model used to study different forms of bone metastases poses a constraint in the development of pharmacological treatments. There are a limited number of animal models that exhibit spontaneous bone metastases. The prevailing models include the introduction of cancer cells either into the bloodstream or directly into the bone [18, 61, 198, 199]. These models fail to accurately reproduce the processes occurring in cancer development, thereby restricting the potential therapy strategies.

Table 2.A concise summary of the therapeutic strategies targeting growth factor receptors (GFRs) in bone metastases.
Target Agent Effectiveness & Observations Model/Study References
FGF/FGFR AZD4547 Inhibits FGFR signaling & proliferation in FGFR-abnormal tumors. Suppresses osteoclastogenesis & tumor-induced osteolysis. Orthotopic breast cancer & pancreatic cancer PDX model in mice. [19, 172, 173]
EGF/EGFR TKIs, mAbs, Osimertinib Varied effectiveness in HER-driven pathways. Osimertinib showed notable efficacy against bone metastases in EGFR-mutant lung adenocarcinoma. NSCLC patients & mouse model of intratibial human NSCLC. [174, 175, 176, 177, 178, 179, 180, 181, 182]
TGFβ/TGFβR TGFβR I kinase inhibitor, 1D11 antibody, Halofuginone (HF) Inhibition of TGFβ signaling reduces bone metastases. HF decreases bone damage in breast and prostate cancer models. Various cancer models & mouse model of breast and prostate cancer. [17, 18, 61, 144, 185]
VEGF/VEGFR β2AR, TAS-115, Cabozantinib β2AR stimulation reduced metastatic lesion size. TAS-115 & Cabozantinib show promise in prostate cancer and renal cell carcinoma bone metastases. Mouse model of breast cancer & prostate cancer, phase III METEOR trial. [187, 188, 189, 190, 191, 192, 193]

TKIs, tyrosine kinase inhibitors; NSCLC. non-small cell lung cancer.

7. Future Directions

Future research should focus on advancing targeted therapies against specific growth factor receptors involved in bone metastases. This includes further exploration of the molecular mechanisms underpinning the interaction between tumor cells and the bone microenvironment. The ‘vicious cycle’ of bone destruction and tumor growth, driven by factors like parathyroid hormone-related peptide and transforming growth factor β, offers rich avenues for therapeutic intervention. Investigating signaling molecules such as receptor activator of nuclear factor κB ligand, Src kinase, and cathepsin K, which regulate osteoclast function, and chemokine receptor 4, involved in the homing of tumor cells to bone, could lead to novel treatments that mitigate destructive bone metastases​​.

To effectively address the future directions concerning growth factors involved in bone metastases, it is of utmost importance to concentrate on individual growth factors and their specific functions. For example, the targeting of Transforming Growth Factor Beta (TGFβ) could entail the development of inhibitors that hinder its pro-metastatic impact on tumor cells within the bone microenvironment. Similarly, the examination of Bone Morphogenetic Proteins (BMPs) may strive to clarify their dual roles in promoting bone formation and supporting tumor growth, with the goal of utilizing these proteins for therapeutic advantages. Every growth factor, like VEGF, PDGF, TGF and FGFs, possesses different mechanisms that can be used for targeted therapy. This aims to disrupt the interaction between the tumor and the bone, inhibit tumor growth, and prevent bone metastasis.

Another critical area for future research is the development of novel modalities for predicting and monitoring treatment responses in bone metastases. This entails not only refining existing therapeutic approaches but also discovering biomarkers that can precisley predict the efficacy of targeted therapies. Emphasizing personalized medicine, research should aim to tailor treatments based on individual patient profiles, considering the specific growth factor receptor pathways active in their cancer. Future research should also emphasize the intricate interplay among these growth factors, exploring combination therapies that target multiple pathways to enhance the effectiveness of treatment and overcome resistance.

8. Conclusions

In conclusion, our expedition through the realm of growth factors and bone metastases marks not an end, but a beginning. It beckons a future where the intricacies of molecular interactions are not just understood but harnessed, where targeted therapies become not just a possibility but a reality, and where the specter of bone metastases is met with not just hope but tangible, effective treatments. As we approach these groundbreaking advancements, our determination grows stronger, our curiosity intensifies, and our commitment to overcoming this significant challenge remains steadfast. This manuscript, therefore, serves as both a testament to our current understanding and a clarion call to the scientific community: the journey continues, and the fight against bone metastases marches on, fueled by innovation, perseverance, and the unyielding spirit of scientific discovery.

Author Contributions

KSM and SAA, Conceptualization, writing, and editing. Both authors contributed to editorial changes in the manuscript. Both authors read and approved the final manuscript. Both authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Ethics Approval and Consent to Participate

Not applicable.

Acknowledgment

Not applicable.

Funding

This research received no external funding.

Conflict of Interest

The authors declare no conflict of interest.

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