Academic Editor: Mateusz Maciejczyk
Older individuals are more likely to develop solid cancers, but at the same time are more sensitive to the side effects of chemotherapy. In addition, older adults are more likely to present with chronic diseases (comorbidities) and immunosenescence that may decrease immunosurveillance against cancer. Clinical outcomes for the older patient with cancer are different from the younger patient and require different research and treatment approaches. Thus, alternative therapeutic approaches tailored specifically to the older patients are required. Colorectal cancer (CRC) has a high incidence in older individuals and is the third leading cause of cancer death globally. Anti-hypertensives are used by a large proportion of older patients and some studies have pointed to a positive impact of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) on CRC outcomes. As we have previously shown in a mouse model, lung metastases express ACE and contain many infiltrating myeloid-derived suppressor cells (MDSC); particularly high levels of MDSC are also present in the blood of older patients with CRC and other cancers, and are associated with disease severity. In this Commentary, we hypothesize that one mechanism responsible for the positive impact of ACEi or ARB on the outcome of CRC is the modulation of myeloid cells contributing to their maturation to non-suppressive neutrophils/monocytes and diverting them away from retaining an immature MDSC phenotype.
Increasing life expectancy in most countries is linked to improvements in
prevention and treatment of non-transmissible diseases and vaccination against
transmissible diseases. It has been projected that by 2050, one in six people in
the world will be older than 65 years (16%) [1]. Considering that chronological
ageing does not exactly parallel biological ageing, individuals older than 65
years can be healthy or present one or more morbidities (comorbidities) [2] and
chronic diseases lead to disabilities in a great percentage of the ageing
population [3]. Besides the negative impact on activities of daily living of the
older adult, there is an economic burden by the loss to the workforce and
increased medical expenditure [4, 5]. The incidence of most solid cancers is
higher in older individuals and thus cancer has been considered an age-related
disease [6]. Ageing and cancer are cellular and molecular processes sharing
similarities since both are associated with accumulated mutations [7, 8]. The
average age of CRC appearance is 67 years [9] and in patients with metastases,
the one-year survival is 70–75%, 30–35% of patients survive more than 3 years
and only 20% survive for 5 years (reviewed in [10]). The risk of death is
increased in CRC patients from 50 to 74 years of age and is highest in patients
older than 75 [11]. The outcome of older patients with CRC is thought to be
different from young individuals mostly because of increased comorbidities and
immunosenescence. The latter can be described as resulting in decreased immunity
against pathogens and cancer due to changes occurring in the organs of the immune
system which impair the generation and function of immune cells. These
differences commonly encompass disproportionate increases of myeloid cells which
act as immune suppressors (MDSCs). Therefore, immune cell number and function
altered during the ageing process can be assessed and employed as biomarkers [12, 13, 14]. In addition, most of older adults suffer from one or more morbidities
which also impact cancer outcome [15, 16]. The use of five or more drugs for such
morbidities (polypharmacy) is not unusual in the older population, which is an
important point to be considered also in the context of anti-cancer therapy.
Erning et al. [17] surveyed 2735 patients with CRC at age
Amongst older CRC patients, hypertension and cardiovascular disease are quite
common. Data from 2005 to 2008 on 12,648 metastatic CRC patients showed that 52%
were
Prophylaxis with these drugs may also be beneficial. Thus, in patients without
cancer at colonoscopy, the use of ACEi or ARB (for at least 180 days) was
evaluated and correlated with tumor development between 3 and 36 months after the
negative diagnosis. After 3 years of follow-up, patients using ACEi/ARB (n =
30,856, 61–78 years of age) exhibited a significantly lower incidence of CRC
than non-users [21]. Also, a retrospective study with 13,982 patients (
Thus, the overwhelming consensus from large epidemiological surveys is that use
of ACEi/ARB is protective against CRC. The mechanism therefore is not clear, but
may involve an effect of the drugs on MDSCs. Our group (VB and NMF) has
investigated these cells in experimental models of lung cancer and in clinical
cases of CRC [26, 27, 28, 29, 30]. In the urethane-induced lung cancer model, we
found an increased percentage of infiltrating MDSC, high expression of ACE mRNA
and protein in addition to intense expression of ACE protein in tumor nodules in
the lungs [29]. In clinical cases of CRC we observed that MDSCs from peripheral
blood of older patients were present in higher numbers in step with disease
severity (in metastatic disease, 5.35
It has been suggested that targeting MDSCs will be beneficial in anti-tumor therapy to relieve their inhibition of anti-cancer effector activity of T and B cells and reduce their facilitation of the development of T regulatory cells [32, 33]. However, drugs that inhibit MDSC, such as Gemcitabine or 5-fluorouracil [34, 35] may cause bone marrow suppression [36] and other side effects, and may be especially problematic in older patients. Thus, new agents with less toxicity and greater specificity are required. The major mechanisms by which MDSCs inhibit T cells include arginase 1 (ARG1) production and induced nitric oxide synthase (iNOS). These moieties interfere with the metabolism of L-arginine (essential for T cells) and inactivate the T cell receptor (TCR), respectively [37, 38, 39]. Therefore, ARG1 and iNOS are potential targets for reprogramming MDSCs from a suppressive to a pro-inflammatory phenotype. Support for this notion comes from data on CBP/EP300-BRD inhibition of ARG1 and iNOS in a model of colon carcinoma, leading to a delay in tumor growth [40].
As discussed above, the use of ACEi is likely associated with a better outcome in CRC [21, 22, 23, 24, 25] but the mechanisms responsible are not fully understood and it is not yet clear whether the benefit to the patient observed in ACEi users is linked to MDSCs. ACE expression in myeloid cells is reported as a fundamental requirement for normal myelopoiesis, but ACE could also be responsible for myeloid cell modulation during the process of differentiation. In experimental models, Shen et al. [41] found that enforced expression of ACE by monocytic cells led to a decreased percentage of MDSCs within the myeloid lineage. They also observed that transgenic mice overexpressing ACE in myeloid cells displayed decreased numbers of MDSCs in blood and spleen in a tumor model [41]. In a model of mammary carcinogenesis, irradiation and ACEi (captopril) administration delayed tumor growth, reduced the expression of VEGF by tumor cells, and discretely modulated granulocytic MDSCs [42].
Taken together, the findings discussed in this Commentary are consistent with the hypothesis that one of the possible mechanisms associated with a positive impact of ACEi or ARB on the outcome of CRC patients would be via the modulation of myeloid cells contributing to the maturation of neutrophils/monocytes and preventing the acquisition of the immature phenotype associated with the suppressive function of MDSCs.
VB—contributions to conception and design, drafting the manuscript, approved the final version to be published. NMF—contributions to conception and design, critical revision, approved the final version to be published. GP—contributions to conception and design, critical revision, approved the final version to be published.
Not applicable.
Not applicable.
CAPES PrInt UNIFESP 88881.310735/2018-01.
The authors declare no conflict of interest. GP is serving as the Editor-in-Chief of this journal. We declare that GP had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to MM.
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