IMR Press / FBL / Volume 25 / Issue 5 / DOI: 10.2741/4843
Cancer associated fibroblasts: phenotypic and functional heterogeneity
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1 National Institute of Biomedical Genomics, Kalyani, WB, India
Send correspondence to: Sandeep Singh, National Institute of Biomedical Genomics, Kalyani, WB, India, 741251, Tel: 91-8647868383, Fax: 91-33-25892151, E-mail:
Front. Biosci. (Landmark Ed) 2020, 25(5), 961–978;
Published: 1 March 2020
(This article belongs to the Special Issue Elucidation of exosomes role in metastasis)

Cancer associated fibroblasts (CAFs) are the most abundant stromal cell-type in solid tumor-microenvironment (TME) and have emerged as key player in tumor progression. CAFs establish communication with cancer cells through paracrine mechanisms or via direct cell adhesion as well as influence the cancer cell behaviour indirectly by remodelling the extracellular matrix. Although numerous studies have strongly suggested the tumor promoting role of CAFs, few recent reports have revealed the heterogeneity in CAFs. Here, we have summarized the recent findings on the mechanisms related to the heterogeneous behaviour of CAFs serving as positive or negative regulator of tumor progression. Further, reports related to the targeted therapy against CAF-mediated mechanisms are also summarized briefly.

Cancer Associated Fibroblasts
Tumor Microenvironment
alpha-Smooth muscle actin
Cancer Stem Cells

A growing body of evidence suggests that tumor development not only involves the malignant cancer cells but also the cells and the molecules of surrounding stroma, termed as tumor-microenvironment (TME) (1, 2). TME plays important roles in facilitating malignant cancer cells to acquire hallmarks properties through bidirectional communication between cancer cells and the components of TME. TME is composed of cellular component and extracellular matrix (3, 4). The extracellular matrix of TME provides scaffold for its structure. The main components of this are collagens, fibronectins, proteoglycans, elastins, and laminin. Apart from these, other molecules are also trapped inside the matrix. These include matrix metalloproteinases (MMPs) secreted by transformed cancer and cells of the TME (5, 6).The cellular components of tumor microenvironment include the endothelial cells, infiltrating immune cells, pericytes and fibroblasts. In normal tissues, fibroblasts are elongated, spindle shaped cells which are present in the extracellular matrix in a suspended form (3). They provide architectural scaffold to the tissue by secreting components of the extracellular matrix. They help in regulating interstitial pressure and fluid volume and actively involved in the tissue remodelling and wound repair. Within the TME, cancer associated fibroblasts (CAFs) also known as the stromal fibroblasts or tumor associated fibroblasts are the most abundant stromal cell types. CAFs are activated mesenchymal cells present in tumor stroma (7). They are present in almost all the solid tumors in varying proportions and constitute up to 70% volume of the breast, prostate and pancreatic tumors whereas they are present in less proportion in brain, kidney and ovarian cancers (8). These cells interact with tumor cells in a reciprocal manner and are involved in tumor development at each stage. CAFs evolve alongside tumor as it progresses and help the tumor cells to evolve (1, 5). Here, we have reviewed the recent advancement in understanding the mechanisms specifically with respect to diverse phenotypes and function of CAFs.


The origin of CAFs can be highly heterogeneous. The main source of CAFs in the TME is the resident normal fibroblasts which get converted to CAFs. Tumor cells secrete growth factors such as TGFβ1, SDF1 and PDGFRβ to promote conversion of normal fibroblasts into CAFs (9-12). CAFs are recruited to the tumor site in the similar fashion as they are recruited to the site of wound healing. At the site of the wound, platelets migrate and secrete growth factors such as PDGF and TGFβ1 to recruit the normal fibroblasts at the site of injury. The fibroblasts (resident as well as distant) respond to the signals and start migrating to the injury site. After reaching to the injury site, normal fibroblasts acquire activated phenotype under the influence of various growth factors such as TGFβ1. The activated CAFs helps in wound healing process by providing growth factors, cytokines and by producing components of extracellular matrix(13, 14). Unlike the normal wound healing process where activated fibroblasts undergo apoptosis, the activated fibroblasts in tumor stroma do not follow the same fate. They continue to interact with tumor; therefore, tumors are also termed as “wound that never heals” (15, 16).

There are several other sources by which CAFs are found to be originated. CAFs can be generated directly from mesenchymal stem cells (MSCs). MSCs migrate to the tumor site in the similar manner like fibroblasts migration during processes of wound healing. Theses migrating cells have been reported to recruit to the tumor site and differentiate into CAFs. These CAFs express activation marker αSMA, FAP, tenascin-C and thrombosponding-1 in their cytoplasm (17). CAFs can also be generated through the process of epithelial to mesenchymal transition (EMT) from the epithelial cells. CAFs arising through EMT have also been shown to retain genetic alterations of their parental genome. Somatic mutations in the CAFs is debated (18, 19). Though, EMT-derived CAFs may contribute rarely to the total CAF population in tumor, certain reports suggest the accumulation of mutations in CAFs. Mutations in the TP53 and PTEN genes in CAFs isolated from breast cancer is demonstrated helping CAFs to acquire pro-tumorigenic behaviour (20-24). CAFs can also be generated from other cell-types such as pericytes and endothelial cells. These cells can trans-differentiate and contribute to CAFs population. Proliferating endothelial cells can undergo endothelial to mesenchymal transitions under the effect of tumor secreted TGFβ1 to give rise to CAFs (25). CAFs can also be generated from pericytes through the process of pericyte to fibroblast transition (PFT) under the influence of PDGF-BB (26). All these sources of CAFs are not mutually exclusive and may produce a vast heterogeneous population of CAFs within individual cancer-type. This could be the reason for the reported variations in the identification markers for CAFs.

Fibroblasts express various cell surface and intracellular proteins by which they are identified in different tumors. Normal fibroblasts and the CAFs, both being mesenchymal cell type, express vimentin in their cytoplasm. CAFs are identified by expression of fibroblast specific protein 1 (FSP1), also called as S100A4. However, it is also widely expressed by carcinoma cells in different tumor types (27) or due to the process epithelial to mesenchymal (EMT) transition in these cells (28). CAFs are also identified by expression of fibroblast activation protein alpha (FAPα). However, it is also not exclusively expressed only in CAFs but also reported to be expressed by normal fibroblasts and quiescent mesodermal cells (29, 30). CAFs express platelet derived growth factor receptor alpha and beta (PDGFRα/β). However, like other markers, it is also not exclusive for the CAFs as it is expressed by tumor cells undergoing EMT and by vascular smooth muscle cells, myocardial cells and skeletal muscles (31, 32). Expression of CD90/Thy1 has been reported on fibroblasts cells as cell surface marker. Fibroblasts expressing CD90 on their cell surface have been reported to function as myofibroblastic cells compared to CD90 negative fibroblasts. Expression of CD90 can be a potential marker to identify CAFs in TME (33-36). Other markers which are expressed by CAFs are NG2 (neural glial-2), Desmin and discoidin domain receptor-2 (DDR2). CAFs are also identified by expression of stress fibres of αSMA. Activated CAFs express αSMA in their cytoplasm in most of the tumor types (3). Normal fibroblasts express αSMA during wound healing and it is also expressed by smooth muscle cells surrounding the blood vessels, pericytes, visceral smooth muscle cells and cardiomyocytes (37).


Although, only a small percentage of disseminated cancer cells are capable of forming detectable metastatic tumor; it accounts for a significant number of cancer related mortality and morbidity (27). Metastasis involves a number of sequential events. For this process cancer cells must detach from the surrounding cells and intravasate into blood circulation system and lymphatic system, evade immune response, extravasate into the capillary beds of appropriate site and secondary tumor formation (38). The orchestration between tumor and stromal cells through secreted molecules and interactions with matrixes is demonstrated to facilitate the formation into metastatic tumors (1, 39).

The process of intravasation involves direct interactions between cancer cells, stromal cells and ECM. CAFs play significant role in tumor metastasis from the first step of breaching the basement membrane to formation of micrometastasis (40). CAFs can remodel the extracellular matrix by secreting ECM proteins such as collagens as well as ECM degrading enzymes such as matrix metalloproteinases (MMPs) leading to invasion and metastasis (41). Degradation of ECM creates a path for cancer cells to the vasculature (42).

CAFs show distinct expression of genes which are specifically involved in cell adhesion and migration. Also, through matrix remodelling, CAFs help in making the tracks in the stroma and help tumor cells to move to other sites (43). Both these mechanisms collectively facilitate cell migration and invasion. Studies by Y Hassona et al suggested that senescent CAFs secrets active MMP2, which is instrumental to induce keratinocyte dis-cohesion and epithelial invasion into collagen gels in a TGF-β dependent manner (44). They express N-cadherin on their surface which binds with E-cadherin of tumor cells and pulling them along the tracks (33). This help in directional movement of tumor cells which is necessary for successful invasion and metastasis (34). In colorectal cancer, cancer stem cells have been shown to express CD44v6 cell surface marker which facilitates cells to attach to hyaluronan which is the component of extracellular matrix (45). In case of breast tumor, increased stiffness of the matrix correlated with poor survival. Yes associated Protein (YAP) is an important player of mechanotransduction pathway. If the stiffness of ECM is high, it influences the nuclear localization of Yap1 and facilitate activation of CAFs (35). Additionally, CAFs are also shown to express factors required for neoangiogenesis and neolymphogenesis to promote metastasis (36).

CAFs are also shown to induce metastasis through paracrine signalling to induce epithelial to mesenchymal transition (EMT) (46). EMT plays an important role during the course of tumor initiation, malignant progression, metastasis and therapy resistance (47). Loss of epithelial marker E-cadherin and the expression of mesenchymal marker vimentin is a cardinal sign of EMT (48). In a study, CAFs were found to help the premalignant epithelial cells to acquire mesenchymal traits leading to invasion and metastasis whereas fibroblasts isolated from benign mammoplasty failed to do so (49). In prostate cancer, IL-6 secreted by tumor cells recruited CAFs to the tumor niche which secreted metalloproteinase thereby inducing EMT and invasion in cancer cells (50). In pancreatic ductal adenocarcinoma, IL-6 secreted by CAFs helped tumor cells to undergo EMT and ultimately metastasize. When secretion of IL-6 was inhibited by retinoic acid treatment, the induction of EMT by CAFs was lost (51). In breast cancer, CAFs induce TGFβ/SMAD pathway in breast cancer cells by secreting TGFβ1 leading to EMT mediated invasion and metastasis. This effect was reversed when secretion of TGFβ1 was blocked (52). Study has shown that CAFs secrete some pro-invasive factors in hepatocellular carcinoma and activate TGF-β/PDGF signaling crosstalk to support the process of EMT and transform into an invasive phenotype. Additionally, co-transplantation of myofibroblasts with Ras-transformed hepatocytes strongly enhanced the growth of tumor. However, genetic-interference of PDGF signaling pathway reduced tumor growth and EMT (53). Another recent study suggested that CAFs secret IL32 which promotes breast cancer cell migration by binding to integrin β3 through RGD motif. Interaction between IL32 & integrin β3 induced P38-MAPK signaling pathway, resulting in enhanced EMT marker expression and promote invasion (54).

The rate and type of EMT within a tumor is not differ within the population of tumor cells. Different EMT population is shown to exist in distinct tumor regions associated with a specific microenvironment in skin SCC and mammary tumors (13). Additionally, other cell types within stroma may also play crucial role during the process of EMT. In vivo depletion of macrophages in skin and mammary primary tumours helped in increased population of EpCAM+ epithelial tumor cells and inhibition of the EMT process (14, 15).


As discussed before, CAFs facilitate tumor growth by secreting growth factors and cytokines/chemokines and remodel extracellular matrix. Tumor cells interact with CAFs in a reciprocal manner and activate them to acquire pro-tumorigenic functions. Intriguingly, CAFs were shown to initiate malignant properties in morphologically and genotypically normal epithelial cells. Olumi et al., showed that CAFs through its secreted factors could promote tumor progression in an immortalized but non-tumorigenic prostate cell whereas normal fibroblasts were failed to do so (55). CAFs secrete various factors such as hepatocyte growth factors (HGF), stromal derived growth 1 (SDF-1) and TGFβ1 which modulate the tumor progression (56-58). CAFs isolated from breast tumors could promote breast tumor growth efficiently compared to matched normal fibroblasts. This increased tumor growth was associated with SDF1 secreting-CAFs which promoted angiogenesis through recruitment of endothelial progenitor cells at tumor sites (56, 59). CAFs secretes VEGF which helps in formation of new blood vessels to supply and manage cellular metabolites (60). CAFs interact with other cells in the stroma such as endothelial and inflammatory cells. It alters their functions of secreting chemokines such as monocyte chemotactic protein 1 (MCP1) and interleukins such as IL-1 which affect the functioning of inflammatory cells (61, 62).

CAFs have been shown to affect the stem cell-like properties of tumor cells of different origins. CAFs promote lung tumor cells to undergo dedifferentiation and acquire the stem cell-like properties. To study the effect, Chen et al., established a co-culture model of CAFs and lung cancer cells. CAFs were isolated from lung cancer patients and used as feeder layer. Study showed that CAFs regulate stem cell-like properties in a paracrine manner by expressing IGF-II in the TME and increase Nanog expression in tumor cells expressing IGF1R. Blocking IGF-II/IGF1R signalling affected the expression of Nanog resulting in loss of stem cell characteristics. Lung cancer cells when grown in co-culture with CAFs demonstrated enhanced capacity of self-renewal shown by sphere formation assay and expressed stem cell markers Oct4/Nanog. The effect was not seen when the tumor cells were grown with normal fibroblasts (63). Stassi et al, have reported in colorectal cancer that CAFs secrete growth factors OPN, HGF, and SDF1 which helped colorectal cancer cells to acquire the CD44v6 phenotype as well as cancer stem cell-like phenotype by activating Wnt/β-catenin pathway. CD44v6 expressing colorectal cancer stem cells showed increased migration and metastasis. Colorectal cancer patients with low CD44v6 expression predicted better survival than with high CD44v6 patients (64). In breast cancer, tumor cells educate stromal fibroblasts to express chemokine ligand 2 (CCL2). CCL2 stimulated tumor cells, expressed NOTCH1 and showed cancer stem-like cells phenotype such as increased self-renewing ability shown by sphere formation assay. In this study, patients with increased CCL2-NOTCH1 expression showed grade of poorly differentiated breast cancer tissues (65).

Burman et al., have studied the role of CAF-CSC interaction in prostate cancer. They developed conditional PTEN-deleted mouse model of prostate adenocarcinoma to study reciprocal role of CAFs and cancer stem-like cells isolated from this model. The isolated epithelial cells showed the characteristics of stem-like cancer cells and expressed established markers of CSC as well as demonstrated self-renewing abilities under in vitro conditions. CAFs isolated from the same mouse, significantly promoted stem cell-like properties in CSC including better sphere forming ability (66). Wang et al, have studied the role of CAFs in breast cancer progression. CAFs secreted chemokine (C-C motif) ligand 2 induced NOTCH1 expression in breast cancer cells and helping them to acquire cancer stem cell features. Fibroblasts co-cultured with breast cancer cells promoted stem cell like features in breast cancer cells compared to normal fibroblasts cells. Breast cancer cells secreted cytokines induced CCL2 expression in CAFs activating STAT3 in CAFs (65). In another study, cancer associated fibroblasts from esophageal squamous cell carcinoma (ESCC) secreted IL-6 which conferred chemoresistance to ESCC cells by upregulating C-X-C motif chemokine receptor 7 (CXCR7). Silencing of CXCR7 in ESCC cells significantly decreased the stem cell related gene expression suggesting the involvement of CXCR7 in stemness (67).

In addition, CAFs have been shown to directly affect the sensitivity of cancer cells towards therapeutic agents. Golub et al have reported resistance to RAF-inhibitors in BRAF-mutant melanoma cells mediated through HGF secreted from stromal microenvironment (68). Similar observations were reported by Delorenzi et al., they have found that increased stromal gene expression signature confers resistance to widely used drugs such as 5-fluorouracil and other drugs (69). Karin et al co-cultured CAFs with HNSCC and showed that soluble factors from CAFs help tumor cells to acquire resistance to cetuximab (70). CAFs secreted high mobility group box 1 (HMGB1) helped breast cancer cells to develop resistance against doxorubicin (71). Gemcitabine resistant CAFs in PDAC secrete exosomes with SNAIL which help tumor cells in proliferation and drug resistance (72). These studies demonstrate the potential of CAFs in the development of drug resistance to tumor cells to most commonly used anticancer drug.


Apart from tumor-promoting role, CAFs have also been shown to harbour tumor-restraining functions (73, 74). In pancreatic ductal adenocarcinoma (PDAC), tumor cells secrete sonic hedgehog (Shh) and direct fibroblasts cells to form a desmoplastic rich stroma. Shh-deficient tumors showed reduced stroma and aggressive, proliferating and more vascular tumors (75). In another study, Özdemir et al. generated transgenic mice with ability to delete αSMA-positive cells in PDAC. Depletion of αSMA-positive cells gave rise to invasive and undifferentiated tumors with increased hypoxia and EMT as well as increased cancer stem cells behaviour. Further, PDAC patients with low αSMA-positive cells showed decreased survival (76). CAFs expressing FSP1 have been shown to inhibit tumor development by encapsulating carcinogen. Here, FSP1+ve fibroblast cells helped in limiting the exposure of epithelial cells to carcinogen which could otherwise resulted in DNA damage and tumor development (43).

Further to these findings, elegant work reported by D.A. Tuveson and colleagues has demonstrated spatially separated distinct populations of inflammatory fibroblasts (iCAFs) and myofibroblasts (myCAFs) in PDACs. myCAFs were found to be dependent on the juxtacrine interactions with cancer cells and were located in the peri-glandular region; whereas iCAFs were distantly from cancer cells and myCAFs populations in PDA and were induced by secreted factors from cancer cells through paracrine manner. iCAFs produced IL6, IL11 and LIF and stimulated STAT pathway in cancer cells; whereas, myCAFs were defined by high-αSMA expression. This study predicted the pro and antitumorigenic properties of CAF-subpopulations within the tumors (77). More recently, tumor secreted IL-1 is found to upregulates LIF which ultimately promote CAFs to gain inflammatory phenotype by activating JAK/STAT downstream molecules, whereas TGFβ is shown to work oppositely by downregulating IL-1R1, which induces myofibroblast phenotype in CAFs in PDACs (78).

Daniela et al., have shown functional heterogeneity among CAFs subpopulations. They established two types of CAFs from OSCC patients, CAF-N with transcriptome and secretome similar to normal fibroblasts and CAF-D with different expression pattern than normal fibroblasts. Both CAFs promoted tumor growth in NOD/SCID mice but CAF-N were more tumor-promoting than CAF-D. CAF-N showed more motile phenotype and inhibition of motility reduced the invasion of oral tumor cells. CAF-D were less motile and higher TGFβ1 secreting CAFs help to obtain EMT phenotype in oral tumor cells. Inhibiting TGFβ1 secretion in CAF-D, reduced keratinocyte invasion (79).

Recently, we have demonstrated the presence of two, functionally heterogeneous subtypes of CAFs in established cell cultures and primary human tumor samples of gingivobuccal-oral cancer. The low- or high-αSMA score in tumor stroma has been shown to correlate with better or poor survival of patients respectively. Gene expression pattern based unsupervised clustering analysis resulted in identification of two subtypes of CAFs which were named as C1-type or C2-type CAFsQ. The C1-type CAFs demonstrated low-αSMA (non-myofibroblastic) phenotype compared to C2-type CAFs with myofibroblastic phenotype. Co-culture experiments between C1-type of CAFs and oral cancer cells exhibited higher percentage of proliferating cells with concomitant lower frequency of stem-like cancer cells, compared to the co-culture with C2-type CAFs. Our study has indicated that a small set of differentially expressed genes between these subtypes of CAFs may be responsible for their characteristics and distinct functions in oral tumors. Importantly, BMP4 expression by C1-type CAFs was found as one of the possible mechanisms for suppressed stemness and CAFs-mediated protective role in gingivobuccal tumors (80).

As discussed above, fibroblasts are shown to undergo myofibroblastic differentiation upon TGFβ stimulation (6, 81). In our study, several genes which were differentially upregulated in C2-type CAFs were related to TGFβ-pathway activation (80). Therefore, here we have examined if TGFβ stimulation can induce transition of C1-type CAFs to C2-type CAFs and the transitioned CAFs can reciprocate differently in maintaining stemness of oral cancer cells. We stimulated C1-type CAFs with 10ng/ml TGFβ for 48 hours and determined the myofibroblastic differentiation of CAFs by αSMA stress fibre formation (6, 82). As expected, TGFβ stimulated CAFs expressed more stress fibres suggesting that they can be activated by TGFβ treatment (Figure 1A). Next, we tested whether TGFβ-stimulated myofibroblastic CAFs act similarly as C2-type CAFs with increased stemness in oral cancer cells (80). TGFβ-stimulated or unstimulated CAFs were co-cultured with SCC029b oral cancer cells for 4 days in low-serum media and compared for the frequency of cancer cells with high aldehyde dehydrogenase activity by Aldefluor assay. Interestingly, oral cancer cells demonstrated significantly higher frequency of ALDH-Hi cells upon co-culture with TGFβ-induced myofibroblastic (C2-type) CAFs as compared to non-myofibroblastic (C1-type) CAFs (Figure 1B and C). Overall, data indicates that the microenvironmental TGFβ may be one of the responsible factors for heterogeneity in stromal CAFs determining the presence of tumor suppressive or supportive type CAFs in oral tumor tissues.

Figure 1

(A) Expression of αSMA was analyzed after treatment with TGFβ. Images were taken at x200 magnification. (B) TGFβ stimulated cells were co-cultured with SCC029b for 4 days in low serum media. Frequency of ALDH-Hi cells were determined by flow cytometry using Aldefluor assay and shown as dot plots. (C) Bar graph represents the average frequency of ALDH-Hi cells from three biological repeats. p value was calculated by Student’s t-test.


Surgery and radiotherapy are the major treatment strategies for solid cancers. Combining both treatment modality have provided improved outcomes for patients (83). Since, TME plays crucial role in tumorigenesis, it offers a great opportunity to therapeutically target these cells. Strategies have been made to specifically target different components of TME. CAFs being the major components of TME, draws major attention in this direction. Head and neck cancer patients with higher score for αSMA expression in tumor stroma are associated with decreased disease free and overall survival; suggesting CAFs as plausible target for these patients (84). Lee and Gilboa et al., have shown that targeting FAP expressing CAFs, could inhibit tumor formation ability in mice which were immunized against FAP (57). Similar approach was adopted by Loeffler and Reisfeld. They constructed oral DNA vaccine against FAP and demonstrated that CD8+ T-cell mediated targeting of FAP expressing CAFs suppressed tumor formation and metastatic ability of multidrug resistant colon and breast carcinoma (58). Wen and Nakamura, have shown that inhibition of tumor-stroma interaction by specifically targeting HGF by NK4 impaired the colon cancer growth and liver metastasis (76). Targeting HGF by monoclonal antibody could reduce glioma formation in murine models (85).

Immune evasion is one of the major hallmark characteristics of tumors. CAFs contribute in acquiring these characteristics and they could be used as a target for immunotherapy. Fujiwara et al., recently reported that CAFs regulated infiltrating lymphocytes by IL-6 and blocking IL-6 or targeting CAFs could improve immunotherapy (86). FAPα is a marker of CAFs and has been utilized as target in immunotherapy directed against CAFs (87). Targeting FAP positive CAFs in PDAC helped the antitumor activity of α-CTLA-4 and α-PD-L1 which ultimately helped T cells to move to TME and act on tumor cell clearance (30). Hanks et al., have shown in melanoma that inhibition of TGFβ in CAFs resulted in an increase in the number of CAFs and MMP-9 secreted from CAFs cleaved PD-L1 resulting in development of anti-PD-L1 resistance (88).

Very recently, Hynes et al., have shown the differential function of extracellular matrix proteins based on their source of origin in PDAC of mouse and human tumors. Their group suggested that ECM-protein matrisome derived from tumor cells correlated with poor prognosis compared to majority of ECM-protein matrisome derived from stromal cells showed both pro- and anti-tumorigenic behaviour. The IPA analysis showed that tumor-cell ECM proteins were regulated by FGF10, FAK1, EGF and MAP2K1 while stromal-cell ECM proteins were regulated by α-catenin, AHR, BIRC5 and SMAD3 (89). Similarly, Carvalho et al., has reported cancers with mutations in BRAF, SMAD4 and TP53 mutation and MYC amplification activated a distinct ECM transcription profile which correlated with poor prognosis and immunosuppressive behavior (90).

There are various chemotherapeutic drugs are being tested for targeting stromal compartment. Sibrotozumab is antagonist of FAP and functions by inhibiting CAF differentiation (91). AMD-3100 and IPI-926 target SDF1/CXCL2 and smoothen of sonic hedgehog pathway, respectively and demonstrated to impair the tumor-stroma crosstalk in multiple myeloma, Non-Hodgkin’s lymphoma and pancreatic cancer (1, 92). Specifically targeting the stromal and its derived components such as PDGF-C, Tenascin-C, and COX-2 has been tested in model systems of multiple myeloma, PDAC, and astrocytoma and Non-Hodgkin’s lymphoma with exciting results (67). Targeting NOX4 by RNA interference or by pharmacological inhibition impairs the trans-differentiation of CAFs with reduced tumor growth (93).

The clinical trials to target CAFs have been attempted with few degree of success. The iodine 131-labeled monoclonal antibody F19 (131I-mAbF19) which targets FAP in colon cancer has proved to be useful in diagnostics therapeutics (94). The phase III trial has been done for Bevacizumab against malignant pleural mesothelioma and it has shown improvement in overall survival of the patients (95). A phase II trial of Ruxolitinib, an inhibitor of myelofibrosis, was done for PDAC patients. The results suggest that it affects directly to tumors and it is also effective in those patients who have systemic inflammation (96).

These studies provide an opportunity to intervene stromal fibroblasts leading to cancer therapy, although they present a great challenge to carefully design the patient trails (97, 98). Various strategies to target CAFs in TME is depicted in Figure 2.

Figure 2

Targets against CAFs in tumor microenvironment: Direct depletion of cancer associated fibroblasts (CAFs) via immunotherapies / chemotherapies or targeting crucial signals responsible for CAFs-mediated function can be adapted as approach in CAFs-directed anticancer strategies. FAP, fibroblast activation protein; mAB, monoclonal antibody; HGF, hepatocyte growth factor; SDF1, stromal-derived factor1; CXCL-2 (C-X-C motif) ligand 2.


Collectively, we have highlighted the recent findings on the mechanisms of CAFs mediated role in tumor progression (Table 1). Due to their pro-survival or pro-metastatic functions, CAFs have become an attractive target for achieving more effective response of standard treatment. However, caution has to be applied in targeting CAFs as uniform cell type. we discussed that the stromal components of the tumor may also evolve side by side along with the cancerous cells. The stromal cells upon getting distinct instructions from other components of tumor in the form of cytokines, chemokines or growth factors may give rise to heterogeneous population of CAFs with distinct phenotype and functions. The traditional view of considering the CAFs as pro-tumorigenic niche has been recently challenged in some tumor types. Clearly, more basic research is needed in comprehending the role of heterogeneous subpopulations of CAFs. Reciprocation between various other cellular and non-cellular components during the course of tumor evolution may lead to high degree of dynamic complex interactions. Therefore, deeper molecular characterization specifically from the patient samples may lead to define the cellular subsets of CAFs. Overall, understanding the heterogeneity in CAFs subpopulations and related complexity in reciprocal cross-talk within TME may possibly provide best treatment advantage to cancer patients.

Table 1 Functions of CAFs in tumor microenvironment
Sl. No. Functions References
1 Invasion and Metastasis (33, 34, 40, 43)
2 Extracellular matrix remodeling (41, 42)
3 Secretion of MMP (44)
4 Attachment to the matrix (45)
5 Angiogenesis (36, 60)
6 Epithelial to mesenchymal transition (EMT) (49-54)
7 Stemness (1, 63-67, 85, 92)
8 Growth Factor secretion (55-59, 61, 62, 64, 65)
9 Drug Resistance (68, 69, 70, 71, 72)
10 Anti-tumorigenic (43, 73, 75, 76, 74)

This work was supported by the grant received from Wellcome Trust-DBT India Alliance (#IA/I/13/1/500908) and NIBMG-intramural grant. AKP thank ICMR, India for fellowship support.

HanahanDCoussensL. MAccessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer cell2012213309322DOI: 10.1016/j.ccr.2012.02.022 PMid:22439926
Vaupel P Kallinowski F Okunieff P Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer research 1989 49 23 6449 6465
KalluriRZeisbergMFibroblasts in cancer. Nature Reviews Cancer200665392DOI: 10.1038/nrc1877 PMid:16572188
VerfaillieC. MAdult stem cells: assessing the case for pluripotency. Trends in cell biology20021211502508DOI: 10.1016/S0962-8924(02)02386-3
BalkwillF. RCapassoMHagemannTThe tumor microenvironment at a glance. In: The Company of Biologists Ltd, Journal of Cell Science2012DOI: 10.1242/jcs.116392 PMid:23420197
KessenbrockKPlaksVWerbZMatrix metalloproteinases: regulators of the tumor microenvironment. Cell201014115267DOI: 10.1016/j.cell.2010.03.015 PMid:20371345 PMCid:PMC2862057
KalluriRThe biology and function of fibroblasts in cancer. Nature Reviews Cancer2016169582DOI: 10.1038/nrc.2016.73 PMid:27550820
GascardPTlstyT. DCarcinoma-associated fibroblasts: orchestrating the composition of malignancy. Genes & development201630910021019DOI: 10.1101/gad.279737.116 PMid:27151975 PMCid:PMC4863733
GallagherP. GBaoYProrockAZigrinoPNischtRPolitiVMauchCDragulevBFoxJ. WGene expression profiling reveals cross-talk between melanoma and fibroblasts: implications for host-tumor interactions in metastasis. Cancer research2005651041344146DOI: 10.1158/0008-5472. CAN-04-0415 PMid:15899804
BuessMNuytenD. S. AHastieTNielsenTPesichRBrownP. OCharacterization of heterotypic interaction effects in vitro to deconvolute global gene expression profiles in cancer. Genome biology200789R191DOI: 10.1186/gb-2007-8-9-r191 PMid:17868458 PMCid:PMC2375029
KojimaYAcarAEatonE. NMellodyK. TScheelCBen-PorathIOnderT. TWangZ. CRichardsonA. LWeinbergR. AAutocrine TGF-β and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proceedings of the National Academy of Sciences2010107462000920014DOI: 10.1073/pnas.1013805107 PMid:21041659 PMCid:PMC2993333
MuellerLGoumasF. AAffeldtMSandtnerSGehlingU. MBrilloffSWalterJKarnatzNLamszusKRogiersXStromal fibroblasts in colorectal liver metastases originate from resident fibroblasts and generate an inflammatory microenvironment. The American journal of pathology2007171516081618DOI: 10.2353/ajpath.2007.060661 PMid:17916596 PMCid:PMC2043521
StellosKKopfSPaulAMarquardtJ. UGawazMHuardJLangerH. FPlatelets in regeneration. Semin Thromb Hemost2010362175184DOI: 10.1055/s-0030-1251502 PMid:20414833
GawazMVogelSPlatelets in tissue repair: control of apoptosis and interactions with regenerative cells. Blood20131221525502554DOI: 10.1182/blood-2013-05-468694 PMid:23963043
Desmouliere A Redard M Darby I Gabbiani G Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar. The American journal of pathology 1995 146 1 56
SingerA. JClarkR. ACutaneous wound healing. New England Journal of Medicine199934110738746DOI: 10.1056/NEJM199909023411006 PMid:10471461
SpaethE. LDembinskiJ. LSasserA. KWatsonKKloppAHallBAndreeffMMariniFMesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. PloS one200944e4992DOI: 10.1371/journal.pone.0004992 PMid:19352430 PMCid:PMC2661372
AllinenMBeroukhimRCaiLBrennanCLahti-DomeniciJHuangHPorterDHuMChinLRichardsonAMolecular characterization of the tumor microenvironment in breast cancer. Cancer cell2004611732DOI: 10.1016/j.ccr.2004.06.010 PMid:15261139
QiuWHuMSridharAOpeskinKFoxSShipitsinMTrivettMThompsonE. RRamakrishnaMGorringeK. LNo evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas. Nature genetics2008405650DOI: 10.1038/ng.117 PMid:18408720 PMCid:PMC3745022
HillRSongYCardiffR. DDykeT. VanSelective evolution of stromal mesenchyme with p53 loss in response to epithelial tumorigenesis. Cell2005123610011011DOI: 10.1016/j.cell.2005.09.030 PMid:16360031
KuroseKGilleyKMatsumotoSWatsonP. HZhouX.-PEngCFrequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nature genetics2002323355DOI: 10.1038/ng1013 PMid:12379854
Moinfar F Man Y. G Arnould L Bratthauer G. L Ratschek M Tavassoli F. A Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: implications for tumorigenesis. Cancer research 2000 60 9 2562 2566
RadiskyD. CKennyP. ABissellM. JFibrosis and cancer: do myofibroblasts come also from epithelial cells via EMT? Journal of Cellular Biochemistry20071014830839DOI: 10.1002/jcb.21186 PMid:17211838 PMCid:PMC2838476
RadiskyD. CLevyD. DLittlepageL. ELiuHNelsonC. MFataJ. ELeakeDGoddenE. LAlbertsonD. GNietoM. ARac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. nature20054367047123DOI: 10.1038/nature03688 PMid:16001073 PMCid:PMC2784913
ZeisbergE. MTarnavskiOZeisbergMDorfmanA. LMcMullenJ. RGustafssonEChandrakerAYuanXPuW. TRobertsA. BEndothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nature medicine2007138952DOI: 10.1038/nm1613 PMid:17660828
HosakaKYangYSekiTFischerCDubeyOFredlundEHartmanJReligaPMorikawaHIshiiYPericyte-fibroblast transition promotes tumor growth and metastasis. Proceedings of the National Academy of Sciences201611338E5618E5627DOI: 10.1073/pnas.1608384113 PMid:27608497 PMCid:PMC5035870
FeiFQuJZhangMLiYZhangSS100A4 in cancer progression and metastasis: A systematic review. Oncotarget201784273219DOI: 10.18632/oncotarget.18016 PMid:29069865 PMCid:PMC5641208
OkadaHDanoffT. MKalluriRNeilsonE. GEarly role of Fsp1 in epithelial-mesenchymal transformation. American Journal of Physiology-Renal Physiology19972734F563F574DOI: 10.1152/ajprenal.1997.273.4. F563 PMid:9362334
Garin-ChesaPOldL. JRettigW. JCell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proceedings of the National Academy of Sciences1990871872357239DOI: 10.1073/pnas.87.18.7235 PMid:2402505 PMCid:PMC54718
FeigCJonesJ. OKramanMWellsR. J. BDeonarineAChanD. SConnellC. MRobertsE. WZhaoQCaballeroO. LTargeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proceedings of the National Academy of Sciences2013110502021220217DOI: 10.1073/pnas.1320318110 PMid:24277834 PMCid:PMC3864274
CuttlerA. SLeClairR. e. JStohnJ. PWangQSorensonC. MLiawLLindnerV Characterization of Pdgfrb-Cre transgenic mice reveals reduction of ROSA26 reporter activity in remodeling arteries. Genesis2011498673680DOI: 10.1002/dvg.20769 PMid:21557454 PMCid:PMC3244048
WeissmuellerSManchadoESaborowskiMMorrisJ. PWagenblastEDavisC. AMoonS.-HPfisterN. TTschaharganehD. FKitzingTMutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor signaling. Cell20141572382394DOI: 10.1016/j.cell.2014.01.066 PMid:24725405 PMCid:PMC4001090
KoumasLSmithT. JFeldonSBlumbergNPhippsR. PThy-1 expression in human fibroblast subsets defines myofibroblastic or lipofibroblastic phenotypes. The American journal of pathology2003163412911300DOI: 10.1016/S0002-9440(10)63488-8
KoumasLSmithT. JPhippsR. PFibroblast subsets in the human orbit: Thy-1+ and Thy-1-subpopulations exhibit distinct phenotypes. European journal of immunology2002322477485DOI: 10.1002/1521-4141(200202)32:2<477::AID-IMMU477>3.0. CO;2-U
MoraesD. ASibovT. TPavonL. FAlvimP. QBonadioR. SSilvaJ. R. DaPic-TaylorAToledoO. AMartiL. CAzevedoR. BA reduction in CD90 (THY-1) expression results in increased differentiation of mesenchymal stromal cells. Stem cell research & therapy20167197DOI: 10.1186/s13287-016-0359-3 PMid:27465541 PMCid:PMC4964048
TrueL. DZhangHYeMHuangC.-YNelsonP. SHallerP. D. VonTjoelkerL. WKimJ.-SQianW.-JSmithR. DCD90/THY1 is overexpressed in prostate cancer-associated fibroblasts and could serve as a cancer biomarker. Modern Pathology201023101346DOI: 10.1038/modpathol.2010.122 PMid:20562849 PMCid:PMC2948633
WendlingOBornertJ. MChambonPMetzgerDEfficient temporally-controlled targeted mutagenesis in smooth muscle cells of the adult mouse. Genesis20094711418DOI: 10.1002/dvg.20448 PMid:18942088
HsuY.-CLiLFuchsETransit-amplifying cells orchestrate stem cell activity and tissue regeneration. Cell20141574935949DOI: 10.1016/j.cell.2014.02.057 PMid:24813615 PMCid:PMC4041217
HanahanDWeinbergR. AThe hallmarks of cancer. Cell200010015770DOI: 10.1016/S0092-8674(00)81683-9
FrankenN. ARodermondH. MStapJHavemanJBreeC. VanClonogenic assay of cells in vitro. Nature protocols2006152315DOI: 10.1038/nprot.2006.339 PMid:17406473
EgebladMWerbZNew functions for the matrix metalloproteinases in cancer progression. Nature Reviews Cancer200223161DOI: 10.1038/nrc745 PMid:11990853
McCullochE. ATillJ. EPerspectives on the properties of stem cells. Nature medicine200511101026DOI: 10.1038/nm1005-1026 PMid:16211027
ZhangJChenLLiuXKammertoensTBlankensteinTQinZFibroblast-Specific Protein 1/S100A4-Positive Cells Prevent Carcinoma through Collagen Production and Encapsulation of Carcinogens. Cancer research201373927702781DOI: 10.1158/0008-5472. CAN-12-3022 PMid:23539447
InternationalI. P. T. of theConsortiumC. G Mutational landscape of gingivo-buccal oral squamous cell carcinoma reveals new recurrently-mutated genes and molecular subgroups. Nature communications20134DOI: 10.1038/ncomms3873 PMid:24292195 PMCid:PMC3863896
AruffoAStamenkovicIMelnickMUnderhillC. BSeedBCD44 is the principal cell surface receptor for hyaluronate. Cell199061713031313DOI: 10.1016/0092-8674(90)90694-A
StranskyNEgloffA. MTwardA. DKosticA. DCibulskisKSivachenkoAKryukovG. VLawrenceM. SSougnezCMcKennaAThe mutational landscape of head and neck squamous cell carcinoma. Science2011333604611571160DOI: 10.1126/science.1208130 PMid:21798893 PMCid:PMC3415217
BelbinT. JSinghBBarberISocciNWenigBSmithRPrystowskyM. BChildsGMolecular classification of head and neck squamous cell carcinoma using cDNA microarrays. Cancer research200262411841190DOI: 10.1038/87004
ChungC. HParkerJ. SKaracaGWuJFunkhouserW. KMooreDButterfossDXiangDZanationAYinXMolecular classification of head and neck squamous cell carcinomas using patterns of gene expression. Cancer cell200455489500DOI: 10.1016/S1535-6108(04)00112-6
DumontNLiuBDeFilippisR. AChangHRabbanJ. TKarnezisA. NTjoeJ. AMarxJParvinBTlstyT. DBreast fibroblasts modulate early dissemination, tumorigenesis, and metastasis through alteration of extracellular matrix characteristics. Neoplasia2013153249262DOI: 10.1593/neo.121950 PMid:23479504 PMCid:PMC3593149
SquierCCoxPHallBEnhanced penetration of nitrosonornicotine across oral mucosa in the presence of ethanol. Journal of oral pathology & medicine1986155276279DOI: 10.1111/j.1600-0714.1986.tb00623.x PMid:3091795
WightAOgdenGPossible mechanisms by which alcohol may influence the development of oral cancer-a review. Oral oncology1998346441447DOI: 10.1016/S1368-8375(98)00022-0
MarurSD'SouzaGWestraW. HForastiereA. AHPV-associated head and neck cancer: a virus-related cancer epidemic. The lancet oncology2010118781789DOI: 10.1016/S1470-2045(10)70017-6
LeemansC. RBraakhuisB. JBrakenhoffR. HThe molecular biology of head and neck cancer. Nature Reviews Cancer20111119DOI: 10.1038/nrc2982 PMid:21160525
HerreroRCastellsaguéXPawlitaMLissowskaJKeeFBalaramPRajkumarTSridharHRoseBPintosJHuman papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study. Journal of the National Cancer Institute2003952317721783DOI: 10.1093/jnci/djg107 PMid:14652239
Olumi A. F Grossfeld G. D Hayward S. W Carroll P. R Tlsty T. D Cunha G. R Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer research 1999 59 19 5002 5011
OrimoAGuptaP. BSgroiD. CArenzana-SeisdedosFDelaunayTNaeemRCareyV. JRichardsonA. LWeinbergR. AStromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell20051213335348DOI: 10.1016/j.cell.2005.02.034 PMid:15882617
WeverO. DeNguyenQ.-DHoordeL. VanBrackeMBruyneelEGespachCMareelMTenascin-C and SF/HGF produced by myofibroblasts in vitro provide convergent pro-invasive signals to human colon cancer cells through RhoA and Rac. The FASEB Journal200418910161018DOI: 10.1096/fj.03-1110fje PMid:15059978
DesmoulièreAGeinozAGabbianiFGabbianiGTransforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. The Journal of cell biology19931221103111DOI: 10.1083/jcb.122.1.103 PMid:8314838 PMCid:PMC2119614
Nakamura T Matsumoto K Kiritoshi A Tano Y Nakamura T Induction of hepatocyte growth factor in fibroblasts by tumor-derived factors affects invasive growth of tumor cells in vitro analysis of tumor-stromal interactions. Cancer research 1997 57 15 3305 3313
FrancescoE. M. DeLappanoRSantollaM. FMarsicoSCarusoAMaggioliniMHIF-1/GPER signaling mediates the expression of VEGF induced by hypoxia in breast cancer associated fibroblasts (CAFs). Breast Cancer Research2013154R64DOI: 10.1186/bcr3458 PMid:23947803 PMCid:PMC3978922
CoussensL. MWerbZInflammation and cancer. nature20024206917860DOI: 10.1038/nature01322 PMid:12490959 PMCid:PMC2803035
YamamotoTEckesBMauchCHartmannKKriegTMonocyte chemoattractant protein-1 enhances gene expression and synthesis of matrix metalloproteinase-1 in human fibroblasts by an autocrine IL-1+ loop. The Journal of Immunology20001641261746179DOI: 10.4049/jimmunol.164.12.6174 PMid:10843667
ChenW.-JHoC.-CChangY.-LChenH.-YLinC.-ALingT.-YYuS.-LYuanS.-SChenY.-J. LLinC.-YCancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling. Nature communications201453472DOI: 10.1038/ncomms4472 PMid:24668028
TodaroMGaggianesiMCatalanoVBenfanteAIovinoFBiffoniMApuzzoTSperdutiIVolpeSCocorulloGCD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. Cell stem cell2014143342356DOI: 10.1016/j.stem.2014.01.009 PMid:24607406
TsuyadaAChowAWuJSomloGChuPLoeraSLuuTLiXWuXYeWCCL2 mediates crosstalk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells. Cancer research, canres.201235672011DOI: 10.1158/0008-5472. CAN-11-3567 PMid:22472119 PMCid:PMC3367125
Liao C.-P Adisetiyo H Liang M Roy-Burman P Cancer-associated fibroblasts enhance the gland-forming capability of prostate cancer stem cells. Cancer research, 0008-5472. CAN- 2010 09 3982
QiaoYZhangCLiAWangDLuoZPingYZhouBLiuSLiHYueDIL6 derived from cancer-associated fibroblasts promotes chemoresistance via CXCR7 in esophageal squamous cell carcinoma. Oncogene2018377873DOI: 10.1038/onc.2017.387 PMid:29059160
FolkmanJAngiogenesis in cancer, vascular, rheumatoid and other disease. Nature medicine19951127DOI: 10.1038/nm0195-27 PMid:7584949
FürstenbergerGMoosR. VonLucasRThürlimannBSennHHamacherJBonebergECirculating endothelial cells and angiogenic serum factors during neoadjuvant chemotherapy of primary breast cancer. British journal of cancer2006944524DOI: 10.1038/sj.bjc.6602952 PMid:16450002 PMCid:PMC2361171
AttwellDMishraAHallC. NO'FarrellF. MDalkaraTWhat is a pericyte? Journal of Cerebral Blood Flow & Metabolism2016362451455DOI: 10.1177/0271678X15610340 PMid:26661200 PMCid:PMC4759679
Benjamin L. E Hemo I Keshet E A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 1998 125 9 1591 1598
BergersGSongSThe role of pericytes in blood-vessel formation and maintenance. Neuro-oncology200574452464DOI: 10.1215/S1152851705000232 PMid:16212810 PMCid:PMC1871727
LuJYeXFanFXiaLBhattacharyaRBellisterSTozziFSceusiEZhouYTachibanaIEndothelial cells promote the colorectal cancer stem cell phenotype through a soluble form of Jagged-1. Cancer cell2013232171185DOI: 10.1016/j.ccr.2012.12.021 PMid:23375636 PMCid:PMC3574187
Bruns C. J Solorzano C. C Harbison M. T Ozawa S Tsan R Fan D Abbruzzese J Traxler P Buchdunger E Radinsky R Blockade of the epidermal growth factor receptor signaling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma. Cancer research 2000 60 11 2926 2935
RhimA. DObersteinP. EThomasD. HMirekE. TPalermoC. FSastraS. ADeklevaE. NSaundersTBecerraC. PTattersallI. WStromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer cell2014256735747DOI: 10.1016/j.ccr.2014.04.021 PMid:24856585 PMCid:PMC4096698
ÖzdemirB. CPentcheva-HoangTCarstensJ. LZhengXWuC.-CSimpsonT. RLaklaiHSugimotoHKahlertCNovitskiyS. VDepletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer cell2014256719734DOI: 10.1016/j.ccr.2014.04.005 PMid:24856586 PMCid:PMC4180632
ShenghuiHNakadaDMorrisonS. JMechanisms of stem cell self-renewal. Annual Review of Cell and Developmental200925377406DOI: 10.1146/annurev.cellbio.042308.113248 PMid:19575646
OgdenG. RAlcohol and oral cancer. Alcohol2005353169173DOI: 10.1016/j.alcohol.2005.04.002 PMid:16054978
CosteaD. EHillsAOsmanA. HThurlowJKalnaGHuangXMurilloC. PParajuliHSulimanSKulasekaraK. KIdentification of two distinct carcinoma-associated fibroblast subtypes with differential tumor-promoting abilities in oral squamous cell carcinoma. Cancer research2013731338883901DOI: 10.1158/0008-5472. CAN-12-4150 PMid:23598279
PatelA. KVipparthiKThatikondaVArunIBhattacharjeeSSharanRArunPSinghSA subtype of cancer-associated fibroblasts with lower expression of alpha-smooth muscle actin suppresses stemness through BMP4 in oral carcinoma. Oncogenesis201871078DOI: 10.1038/s41389-018-0087-x PMid:30287850 PMCid:PMC6172238
MarusykAAlmendroVPolyakKIntra-tumour heterogeneity: a looking glass for cancer? Nature Reviews Cancer2012125323DOI: 10.1038/nrc3261 PMid:22513401
Cines D. B Pollak E. S Buck C. A Loscalzo J Zimmerman G. A McEver R. P Pober J. S Wick T. M Konkle B. A Schwartz B. S Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 1998 91 10 3527 3561
ArgirisAKaramouzisM. VRabenDFerrisR. LHead and neck cancer. The Lancet2008371962516951709DOI: 10.1016/S0140-6736(08)60728-X
BaeJ. YKimE. KYangD. HZhangXParkY.-JLeeD. YCheC. MKimJReciprocal interaction between carcinoma-associated fibroblasts and squamous carcinoma cells through interleukin-1a induces cancer progression. Neoplasia20141611928938DOI: 10.1016/j.neo.2014.09.003 PMid:25425967 PMCid:PMC4240921
CalabreseCPoppletonHKocakMHoggT. LFullerCHamnerBOhE. YGaberM. WFinklesteinDAllenMA perivascular niche for brain tumor stem cells. Cancer cell20071116982DOI: 10.1016/j.ccr.2006.11.020 PMid:17222791
KatoTNomaKOharaTKashimaHKatsuraYSatoHKomotoSKatsubeRNinomiyaTTazawaHCancer-associated fibroblasts affect intratumoral CD8+ and FoxP3+ T cells via IL6 in the tumor microenvironment. Clinical cancer research2018241948204833DOI: 10.1158/1078-0432. CCR-18-0205 PMid:29921731
LiuTHanCWangSFangPMaZXuLYinRCancer-associated fibroblasts: an emerging target of anti-cancer immunotherapy. Journal of hematology & oncology2019121115DOI: 10.1186/1756-8722-1-1 DOI: 10.1186/s13045-019-0770-1 PMid:31462327 PMCid:PMC6714445
ZhaoFEvansKXiaoCDeVitoNTheivanthiranBHoltzhausenASiskaP. JBlobeG. CHanksB. AStromal fibroblasts mediate anti-PD-1 resistance via MMP-9 and dictate TGFβ inhibitor sequencing in melanoma. Cancer immunology research2018DOI: 10.1158/2326-6066. CIR-18-0086 PMid:30209062
TianCClauserK. RÖhlundDRickeltSHuangYGuptaMManiDCarrS. ATuvesonD. AHynesR. OProteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells. Proceedings of the National Academy of Sciences2019116391960919618DOI: 10.1073/pnas.1908626116 PMid:31484774
ChakravarthyAKhanLBenslerN. PBosePCarvalhoD. D. DeTGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure. Nature communications2018914692DOI: 10.1038/s41467-018-06654-8 PMid:30410077 PMCid:PMC6224529
AlltGPericytesJ. Lawrensoncell biology and pathology. Cells tissues organs20011691111DOI: 10.1159/000047855 PMid:11340256
LathiaJ. DHeddlestonJ. MVenereMRichJ. NDeadly teamwork: neural cancer stem cells and the tumor microenvironment. Cell stem cell201185482485DOI: 10.1016/j.stem.2011.04.013 PMid:21549324 PMCid:PMC3494093
BergersGSongSMeyer-MorseNBergslandEHanahanDBenefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. The Journal of clinical investigation2003111912871295DOI: 10.1172/JCI200317929 PMid:12727920 PMCid:PMC154450
WeltSDivgiC. RScottA. MGarin-ChesaPFinnR. DGrahamMCarswellE. ACohenALarsonS. MOldL. JAntibody targeting in metastatic colon cancer: a phase I study of monoclonal antibody F19 against a cell-surface protein of reactive tumor stromal fibroblasts. Journal of clinical oncology199412611931203DOI: 10.1200/JCO.1994.12.6.1193 PMid:8201382
ZalcmanGMazieresJMargeryJGreillierLAudigier-ValetteCMoro-SibilotDMolinierOCorreRMonnetIGounantVBevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. The Lancet20163871002614051414DOI: 10.1016/S0140-6736(15)01238-6
HurwitzH. IUppalNWagnerS. ABendellJ. CBeckJ. TIIIS. M. WadeNemunaitisJ. JStellaP. JPipasJ. MWainbergZ. ARandomized, double-blind, phase II study of ruxolitinib or placebo in combination with capecitabine in patients with metastatic pancreatic cancer for whom therapy with gemcitabine has failed. Journal of clinical oncology201533344039DOI: 10.1200/JCO.2015.61.4578 PMid:26351344 PMCid:PMC5089161
DikshitRGuptaP. CRamasundarahettigeCGajalakshmiVAleksandrowiczLBadweRKumarRRoySSuraweeraWBrayFCancer mortality in India: a nationally representative survey. The Lancet2012379982818071816DOI: 10.1016/S0140-6736(12)60358-4
MonteroP. HPaTelS. GCancer of the oral cavity. Surgical Oncology Clinics2015243491508DOI: 10.1016/j.soc.2015.03.006 PMid:25979396 PMCid:PMC5018209
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