Mediators Connecting Cardiovascular Disease and Cancer: History
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Contributor:
Elisabeta Badila
,
Cristina Japie
,
Ana-Maria Vrabie
,
Adrian Badila
,
Adriana Georgescu

Cardiovascular (CV) diseases and cancer are two of the most common causes of death worldwide.  The pathophysiological overlap between cancer and CV disease is expressed at different levels, including inflammation, oxidative stress, neuro-hormonal activation, clonal hematopoesis and circulating factors. Traditionally, the interest was to find predictors for CV toxicity associated with antineoplastic treatment and to identify these patients in whom chemotherapy would represent a heavy burden. The relationship between cancer and CV diseases is no longer unidirectional. Extracellular vesicles (EVs) could be among the most important biomarkers as they play a decisive role in early identification and determining the CV risk for cancer patients receiving specific treatment for this disease. The preclinical evidence on the bilateral connection between cancer and cardiovascular disease (especially early cardiac changes) through some specific mediators such as EVs  will be discussed here.

  • cardiovascular disease
  • cancer
  • cardio-oncology
  • extracellular vesicles

1. Circulating Factors

The association between heart failure (HF) and cancer was supported initially by experimental studies. In one such study, investigators studied whether certain biomarkers secreted by the failing hearts in mice would promote intestinal tumour proliferation. In this model, HF was the result of induced large anterior s myocardial infarction (MI). The presence of HF resulted in a statistically significant increase in intestinal tumours, both for native and for heterotopically transplanted hearts in mice. Data from the experimental study were extrapolated to a human cohort, which included 180 healthy subjects, and also to approximately 100 patients with chronic HF [1]. The authors selected five proteins considered to be involved in the pathophysiological overlap between HF and cancer, of which SerpinA3, also known as α-1-antichymotrypsin, was increased in patients with HF and promoted cell proliferation in colon tumours. SerpinA3 belongs to the protein superfamily of serine protease inhibitors, which are involved in various inflammatory processes. Data from the literature suggest that levels of serpinA3 predict long-term mortality in patients with HF and are also associated with several cancer types, including colorectal, gastric, breast, liver and prostate cancer [2][3]. This association could have therapeutic implications, as treatment with mineralocorticoid receptor antagonists seems to downregulate the expression of serpinA3, but this needs to be further investigated [4]. Furthermore, the potential effects of serpinA3 on endothelial cell function or cardiac myocytes as contributing to HF and proliferation-associated genes (MCM6, FKBP10 and IGFBP2 in glioma) following activation of MAPK/ERK1/2, PI3K/AKT signalling in endometrial carcinoma are of interest and require further studies [2][5][6].
Other mediators that lie at the intersection of cancer and CV disease are tumour biomarkers, which have established roles in the early detection of different cancer types and for monitoring tumour progression. Moreover, certain tumour biomarkers, such as CA15-3, CEA and CA125 represent independent markers for CV disease and predict all-cause mortality in such patients, suggesting that there is still much to consider about the strong association between cancer and CV disease. One study showed that CA15-3 was strongly associated with CV mortality and HF, even after multivariable adjustment for common risk factors, whereas the correlation with coronary artery disease and stroke was not statistically significant. CEA was also associated with CV mortality, after adjustment for cofounders [7]. Inflammation has arisen as a viable cause both in CV disease and cancer, because correlation between tumour biomarkers and proinflammatory cytokines, such as TNF-α, IL-6 and IL-10, has been identified [8]. In addition, it was demonstrated that CA125 secretion could be enhanced by the inflammatory cytokines IL-1β, TNF-α and the lipopolysaccharide of Escherichia coli [9]. The proposed mechanism by which systemic inflammation affects CA125 concentrations involves JNK molecular pathways [10]. These data support the idea that CV disease and cancer share common ancillary mechanisms and pathways, which should be addressed in the future in order to ensure precise phenotyping of both diseases.

2. Inflammation

Chronic inflammation is involved in both CV disease and cancer. Inflammation is an important part of tumourigenesis, as it contributes to cancer initiation, proliferation and metastasis. The initial evidence for an association between inflammatory markers, CV disease and cancer originated from observational studies.

2.1. Cytokines

Elevated levels of C-reactive protein (CRP), interleukin-1 (IL-1) and interleukin-6 (IL-6) are associated with atherosclerosis and its complications, including plaque initiation, progression and rupture. Increased levels of CRP were also strongly associated with CV disease and cancer mortality [11]. Data from observational studies also revealed that increased levels of IL-6 were associated with both coronary heart disease and cancer [12][13]. However, these seem to be only observational associations, as data from genetic studies argues against a causative role of either CRP or IL-6 in the development of CV disease. IL-1 levels are increased in patients with CV disease, particularly chronic or decompensated heart failure, with increasing levels according to disease severity [14]. The most striking evidence for the role of IL-1 in the development of CV disease and cancer came from the CANTOS trial. In this randomized controlled trial, treatment with canakinumab, a monoclonal antibody targeting IL-1β, decreased the primary end-point (nonfatal MI, nonfatal stroke and CV death) by 15%. This drug was also associated with a decreased incidence and mortality of lung cancer, although this was not a primary outcome [15]. This study represented additional proof that inflammation links CV disease and cancer, acting as a central player in both diseases.
In contrast to cytokines, whose increased levels have been associated with both CV disease and cancer, there are some cytokines, such as IL-10, that play a role in the development of cancer, but with protective effects in CV diseases. Studies have shown that IL-10 has cardioprotective properties in diabetic mice with MI via regulation of heme clearance pathway, by reducing the size of infarction and improving cardiac function [16]. Furthermore, IL-10 improved capillary density, reduced apoptosis and decreased inflammation in the border zone of the infarcted hearts [16]. The anti-inflammatory action of IL-10 was reflected by inhibiting the secretion of other proinflammatory cytokines including TNF-α [11], nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs) [17]. In addition to its involvement in CV diseases, IL-10 could also serve as a biomarker for prognostic diseases or as a treatment target when taking into consideration the elevated concentration in cancer patients versus the healthy ones. High levels of IL-10 were observed in patients with Hodgkin’s lymphoma, gastric, pancreatic and pulmonary cancer, whereas IL-10 levels in patients with colon and renal cancer did not differ significantly from the controls [18][19][20]. Hence, IL-10 is considered an independent prognostic factor and correlates with poor survival.
Another interesting marker that is found at the intersection of hematologic malignancies and CV disease is clonal hematopoiesis of indeterminate potential (CHIP), defined as the presence of somatic mutations in hematopoietic cells, occurring among older persons and in the absence of other hematologic abnormalities. These somatic mutations, most frequently involving the genes DNMT3A and TET2, are involved in DNA methylation and have an established role in the development of myelodysplastic syndromes and acute myeloid leukemia. Moreover, CHIP emerged as a potent, independent risk factor for atherosclerotic CV disease, by regulating pro-inflammatory pathways in monocytes and macrophages, which are known to play important roles in the development of atherosclerosis. The presence of CHIP resulted in an almost two-fold increase in the risk of developing coronary heart disease, after adjustment for common risk factors. The association between CHIP and MI was even more remarkable, with a four-fold increase in the risk of developing early-onset MI for patients with CHIP. This causal association is supported by the results from a murine model, showing that mice engrafted with TET2 bone marrow had more significant atherosclerotic lesions than control mice [21]. Overall, the effect of promoting atherosclerosis is not explained by the opposing enzymatic activities of DNMT3A and TET2 on DNA methylation, but rather it is a marker of their non-enzymatic activity, which is yet to be further explored [22]. Interesting, the ERBB2 protein, or HER2/neu (transmembrane tyrosine kinase receptor), a protein that in humans is encoded by the ERBB2 gene, is implicated in the pathogenesis of multiple cancer types and intersection between cancer and chronic HF [23].
Recent studies have identified new factors called “cachexokines, which could be useful as biomarkers for the diagnosis of cancer-induced cardiac complications and might lead to the identification of new therapeutic targets. Shafer et al. developed a preclinical study and analyzed two types of mouse colon cancer cells that distinguish themselves by their capacity to induce cardiac cachexia [24]. The authors identified a group of seven secreted proteins, collectively called cachexokines (Bridging integrator 1, Syntaxin 7, Multiple inositol-polyphosphate phosphatase 1, Glucosidase alpha acid, Chemokine ligand 2, Adamts like 4 and Ataxin-10), which lead to cardiomyocyte atrophy and aberrant fatty acid metabolism in cardiomyocytes. The simultaneous downregulation of the seven cachexokines on colon cancer cells blocks their capacity to induce cardiac atrophy, whereas the blockage of the single proteins does not influence the cachectic phenotype. The same study showed that ataxin-10 correlates with cachexia, both in mouse models and in pancreatic cancer patients. These findings may pave the way for personalized predictive, diagnostic and therapeutic measures in cancer cachexia.

2.2. Immune Cells

Dysregulation of the immune system is involved in both cancer and CV disease. In cancer, an insufficient or inadequate immune response is responsible for tumour development and progression. The role of the immune system in CV disease is also crucial. Within hours following an acute MI, neutrophils gather in the infarcted area, followed by monocytes and macrophages in subsequent days. The role of cardiac macrophages is also prominent in HF with preserved ejection fraction, promoting cardiac remodelling and fibrosis. In a mouse model of breast cancer, it was showed that MI accelerated tumour cell proliferation, resulting in an approximately two-fold increase in tumour volume and weight at 20 days [25]. This proliferative effect was demonstrated by staining for Ki67+ tumour cells before and after inducing MI, resulting in a doubling of Ki67+ cells in the tumour border of mice with MI versus sham procedure. Further on, the authors attempted to discern the mechanisms by which MI promotes tumour proliferation. They found that MI determines an accumulation of CD11b+Ly6Chi monocytes in tumours, which share similar markers with monocytic myeloid derived suppressor cells, suggesting that MI promotes an immunosuppressive intratumoural response [25]. The authors concluded that MI induces complex epigenetic reprogramming of myeloid cells in hematopoietic reservoirs, resulting in an immunosuppressive phenotype in breast cancer that promotes tumour proliferation [25]. These preliminary results confirmed that dysregulation of the immune system, as a consequence of an acute CV event, influences tumour progression in an animal model. As stated previously, observational studies found an association between MI and cancer development in humans, but these data need further confirmation through rigorous, specifically designed trials.

3. Neuro-Hormonal Activation

Among the complex pathophysiological pathways of HF, renin–angiotensin–aldosterone system (RAAS) plays a central role, initially as a compensatory mechanism, and as the disease progresses, when it becomes maladaptive, leading to cardiac remodelling and sympathetic activation. The main mediator of RAAS, angiotensin II (AngII), which acts by binding to either type 1 Ang II receptor (AT1R) or type 2 Ang II receptor (AT2R), has been associated with detrimental effects, generally promoting cardiac hypertrophy, vasoconstriction and inflammation, or with beneficial effects, including anti-inflammatory and cardio-protective effects, respectively. Similarly, RAAS seems to be involved in cancer pathogenesis, with AngII/AT1R axis promoting tumour cell proliferation, inhibiting apoptosis and creating a pro-inflammatory and immunosuppressive tumour microenvironment. The involvement of RAAS in cancer pathogenesis would naturally raise the therapeutic question whether RAAS blockade with either ACEIs or ARBs would improve cancer survival. The first meta-analysis that investigated the effects of an RAAS blockade on cancer recurrence and survival demonstrated a statistically significant risk reduction of 40% and 25%, with the use of ACEI or ARB [26]. Another meta-analysis indicated a significant improvement in overall survival and cancer-specific survival with the use of RAAS blockers in patients with digestive system malignancies [27]. However, the involvement of RAAS in cancer pathogenesis seems to vary according to cancer type and several studies did not find a beneficial effect of treatment with RAAS inhibitors on cancer survival [26]. There is still much to be understood about the implications of RAAS in the pathophysiology of cancer.

4. Role of Extracellular Vesicles in Cross Talk between CV Disease and Cancer

In recent years, studies have shown that biological fluids display different types of vesicles released by the vast majority of cells, tissues and organs. These vesicles, with the classic general name of extracellular vesicles (EVs), have local or remote effects, participating in various physiological and pathological processes. Interestingly, they appear to maintain bidirectional communication between the heart and other organs and play a particularly important role in cardiac physiology and pathophysiology [28].

4.1. Extracellular Vesicles as Nano Mediators in Cancer and Associated Cardiovascular Disease

EVs are considered potential mediators through which tumour cells communicate with each other and influence their microdomain promoting tumour progression and dissemination, by altering the immune response that subsequently generates cell proliferation, angiogenesis, matrix remodelling and finally metastasis [29][30]. EV contribution to tumour angiogenesis, neovascularization and hypoxia-dependent inter-tumour communication during cancer progression was demonstrated on metastatic brain tumour glioblastoma [31].

Generally, EVs were investigated as biomarkers for initial diagnosis, patient follow up, and, also, for evaluation of tumour response to therapy [32][33][34].

It is now well known that all cells, especially tumour cells, secrete heterogeneous EV subpopulations that vary in size, content, and function. EVs contain on their surface receptors specific to the tumour cells from which they come and specific to the type of cancer. Furthermore, their intravesical content depends on the type and stage of cancer. For instance, during hypoxia, EVs released from cancer cells are enriched in angiogenic factors, such as VEGF and hypoxia-inducible factor 1-alpha (HIF-1α) that promote angiogenesis and later tumour metastasis [35]. In ovarian cancer, EVs carrying VEGF contribute to angiogenesis and metastasis by crosstalk between cancer and endothelial cells [36]. In addition, glioblastoma-specific small EVs are demonstrated to contain the epidermal growth factor receptor variant III (EGFRvIII), the oncogenic mutant variant of EGFR frequently detected in glioblastoma tumours, which stimulates VEGF production and promotes angiogenesis [37]. Interestingly, the EGFRvIII mRNA levels were comparable in large and small EVs isolated from U87EGFRvIII cells, whereas large EVs had higher levels of EGFR protein (EGFRwt + EGFRvIII) compared to small EVs [38]. Thus, EGFRvIII mRNA and protein status can provide glioblastoma-specific liquid biopsy-based monitoring that can help not only diagnose but also evaluate tumour progression [37]. The role of EVs and their miRNA content as diagnostic, prognostic and disease monitoring biomarkers and as nanocarriers for gene therapy in glioblastoma progression and resistance to therapy have been widely debated in a recently published paper [39].

In breast cancer, EVs encompass epidermal growth factor-like repeats and discoidin I-like domains 3 (EDIL3), a glycoprotein that activates the integrin-FAK signaling cascade and plays a crucial role in cancer development [40][41][42]. EDIL3 is also known as a novel regulator of epithelial-mesenchymal transition in clear cell renal cell carcinoma [43]. EDIL3 on EVs also contribute to the enhancement of cell invasion and acceleration of lung metastasis in vivo [40]. Consequently, it was suggested that EDIL3 might be employed as a therapeutic target that limits disease progression.

There are a number of studies that have shown the primary role of EVs in the various stages of cancer and especially in tumour metastases. In addition, the role of EVs in CV pathology is well known and has been studied for a long time.

Very little data concern the involvement of EVs in cardio-oncological pathology, although intuitively, it is becoming increasingly clear that EVs could have a substantial effect.

It is already known that hormone therapies used to treat breast and prostate cancers can raise the risk for a heart attack and stroke. In this case, patient follow-up is very important to identify the first cardiac changes manifested by a reduction of left ventricular ejection fraction, but finding early biomarkers could also have a decisive role in the early treatment of CV diseases. EVs could be one of the key biomarkers, especially since it is known that once released into circulation from apoptotic or activated cells (comprising tumoural cells) can potentially reach any organ, including heart and blood vessels. Furthermore, EVs can be mediators in reverse communication between heart and skeletal muscle, kidneys, bone marrow, lungs, liver, adipose tissue, and brain. In this research direction, the potential of exosomes (small EVs) as diagnostic biomarkers and therapeutic carriers for DOX-induced cardiotoxicity was discussed by Tian et al. in 2021 [44]. DOX, known as a cytotoxic anthracycline antibiotic used to treat several different types of cancer, kills not only tumour cells through circulation but also damages cardiomyocytes at the same time and induces senescence and various death forms of cardiac cells, such as apoptosis, necroptosis, autophagy, pyroptosis and ferroptosis [44].

5. Conclusions and Future Directions

It is becoming more and more clear that patients suffering from cancer end up developing associated heart diseases over time as a result of the specific therapy administered. Because of the alarming increase in the number of patients with cardio-oncological diseases, clinicians and researchers alike are concerned with optimizing clinical results based especially on CV imaging, and finding relevant biomarkers for the early detection of cardiac dysfunction generated by cancer therapy. With reference to CV imaging, echocardiographic assessment of the left ventricular ejection fraction is limited in the sensitive detection of early, subclinical changes in cardiac function. As a result, the recently appearing large cardio-oncological research groups started to develop platforms and different algorithms to investigate novel mechanisms, biomarkers and therapies to improve CV outcomes in cancer patients.

Circulating biomarkers, including EVs (lipid-covered particles), could serve as a measure for identifying early cardiac changes caused by cancer therapy. A series of questions regarding EVs remain unsolved for the time being, one of them being related to the origin of tumour-specific EVs and their distinction from the rest of EVs originating from other activated but non-malignant cells. It is increasingly clear that the investigation of EV-based biomarkers in cross talk between CV disease and cancer is in the beginning stages, but it is becoming a general challenge common to clinicians and researchers. The potential of proteins, miRNAs and other nucleic acids contained in EVs remains to be investigated and to be used later as biomarkers for cardiac toxicity.

In addition to their use as diagnostic biomarkers for early detection of cardiac disorders, EVs can be used as therapeutic vehicles for drugs or regulatory molecules (nucleic acids and proteins) to modulate chemo-resistance of cancer cells and decrease the cardiotoxicity induced by DOX. Furthermore, EVs can be engineered to stimulate immune cells to kill cancer cells, thus decreasing the dosage of DOX and attenuating cardiotoxicity. Because of the many benefits of EVs in cancer therapy and the cardiotoxicity generated by cancer-specific treatment, exploring EV-based therapies in cardio-oncological diseases remains an opportunity for the future.

The ultimate goal of multidisciplinary cardio-oncology teams will be to ensure that cancer patients receive appropriate anti-cancer therapy that minimizes any other CV complication, but also to receive specific treatment for associated heart disease assessed before, during and after cancer therapy.

This entry is adapted from the peer-reviewed paper 10.3390/biom13020321

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