Monocytes link atherosclerosis and cancer

Abstract

From many perspectives, cardiovascular diseases and cancers are fundamentally different. On the one hand, atherosclerosis is a disease of lipid accumulation driven by diet and lifestyle, whereas cancer is an attack “from within” driven by mutations. Nevertheless, studies over the last 20 years have forced us to re-evaluate such a view. We are learning that, among other factors, the immune system is indispensable to the development and progression of both diseases. Its components are not only reactive but can also orchestrate both tumor and atherosclerotic lesion growth. In this Viewpoint, we explore how monocytes, which are key constituents of the immune system, forge links between cardiovascular diseases and cancers.

Introduction

Cardiovascular diseases and cancers are the leading causes of death worldwide. Collectively, they are responsible for nearly two thirds of all deaths in the United States and cost the global economy nearly 2 trillion dollars in direct and indirect costs each year [1, 2]. It is now recognized that inflammation is a major contributor to how these diseases arise, develop and cause death. A groundbreaking paper in 1998 by Charo and colleagues, for example, demonstrated that deletion of CCR2, a chemokine known to drive the accumulation of inflammatory monocytes, attenuates atherosclerosis [3]. More recently, Pollard and colleagues have demonstrated that CCR2-mediated accumulation of inflammatory monocytes is responsible for breast cancer metastasis [4]. These studies illustrate how a common feature, in this case the chemokine receptor-dependent accumulation of a particular monocyte subset, can influence the course of both diseases.

Monocytes are circulating cells that can be separated into at least two functionally distinct subsets. The heterogeneity suggests that subsets are predestined in the blood for particular phenotypes in tissue. Recent research has focused mostly on inflammatory or classical Ly-6C^high CCR2^high monocytes, because these cells selectively expand in experimental models of atherosclerosis and cancer and drive disease progression. Ly-6C^low CCR2⁻ monocytes, which have been called resident, non-classical or patrolling, also require attention as they also accumulate in lesions and regulate tumor angiogenesis [5]. Here, we select a few recent discoveries in cancer and cardiovascular disease that implicate monocytes and discuss how studies in cardiovascular disease can provide insight in cancer and, inversely, how studies in cancer can influence research on cardiovascular disease (Fig. 1).

Fig 1.

Schematic representation of selected monocyte-related processes, which are known to drive atherosclerosis (left) or cancer (right). This Viewpoint proposes to evaluate these and other related findings across diseases.

Role of inflammatory monocytes in cardiovascular disease

Atherosclerosis is an inflammatory chronic disease that leads to myocardial infarction and stroke [6-9]. Advances in basic science over the last 25 years have uncovered a pivotal role for the immune system in mediating all disease stages, from onset to progression and complication. Various leukocytes have been shown to influence atherogenesis. Among these, monocytes and their descendant macrophages are central protagonists. As disease worsens, circulating monocyte number rises whereas in models where monocytes are depleted atherosclerosis does not develop. Monocyte migration to the vessel wall is a key event in the growth of atherosclerotic lesions. Upon accumulation, monocytes differentiate to macrophages and lipid-rich foam cells, which are the key culprits associated with clinical complications [10, 11].

Role of inflammatory monocytes in cancer

Compelling evidence suggests that cell-extrinsic mechanisms mediated by seemingly normal host cells regulate tumorigenesis, growth and metastasis. Monocytes and their lineage descendant macrophages are often the most abundant host cells in the tumor bulk. These cells can be co-opted by carcinoma cells and operate as components of an inflammatory response that construct a supportive stroma [12-14]. Breast cancer grows at a slower pace in mice that lack the macrophage colony stimulating factor M-CSF and, inversely, at a faster pace when M-CSF concentrations are artificially increased [15]. Additionally, most – although not all – clinical studies have reported that the density of tumor-associated macrophages (TAM) correlates with adverse outcomes and shorter survival [16-18]. Although TAM are “plastic” cells and therefore can express distinct phenotypes in different tumor microenvironments and/or at different times during tumor development [16], it is commonly accepted that they critically participate in tumor growth.

What can we learn from research studies on cardiovascular diseases to understand cancer better?

During murine atherosclerosis, Ly-6C^high CCR2^high monocytes expand and accumulate in lesions via CCR2, CCR5 and CX3CR1, whereas Ly-6C^low CCR2⁻ cells accumulate less frequently and do so via CCR5 [19-22]. The expansion of the Ly-6C^high CCR2^high subset is associated with hypercholesterolemia, suggesting that lipids influence monocytopoiesis. As professional phagocytes, monocytes accumulate lipids in the circulation, and thus can function as “Trojan Horses” that bring cholesterol to the growing atheromata [23]. Monocyte subsets are also critical in complications of atherosclerosis such as myocardial infarction. In this case of acute inflammation, inflammatory and proteolytic Ly-6C^high CCR2^high and reparative Ly-6C^low CCR2⁻ monocytes accumulate in the infarcted myocardium sequentially [24]. Many of these accumulate from a recently recognized splenic monocyte reservoir [25].

Regardless of subset, lipid encounter in the vascular wall may be a decisive experience in the life of a lesion-infiltrating monocyte. We have known for years that monocyte-derived macrophages recognize and ingest oxidized lipoproteins via scavenger receptors, and that the ensuing lipid-rich foam cells contribute to the development of a necrotic core, a key feature of a vulnerable plaque [6]. At the molecular level, we now understand that recognition of cholesterol crystals activates the NLRP3 inflammasome that then releases IL-1β [26]. The cytokine is an upstream inflammatory mediator and a contributor to atherosclerosis [27, 28]. Nuclear receptors, known as peroxisome-proliferator-activated receptors (PPARs) and liver X receptors (LXRs), represent another link between lipid metabolism and inflammation. As lipid-activated transcription factors, both PPARs and LXRs integrate metabolic cues and elicit a broad range of effects [29], including the expression of inflammatory genes such as IL1β, IL6 and MCP1, and genes associated with lipid metabolism and cholesterol efflux, such as ABCA1 and ABCG1. These last two also control the proliferation of hematopoietic cells because their deletion leads to severe leukocytosis and monocytosis [30]. Thus, monocytes and their progeny translate metabolic cues to inflammatory signals through engagement of the NLRP3 inflammasome and cholesterol sensing pathways. These findings are important because they identify inducers, sensors, and mediators of inflammation that drive atherosclerosis, and thus represent molecular therapeutic targets.

It is not surprising that much research in the context of atherosclerosis has focused on the intersection between metabolism and inflammation. The disease involves lipid accumulation and metabolic deregulation, and the propensity of these components to accelerate atherogenesis has been appreciated long before it was recognized that inflammation plays a decisive role. In cancer, the influence of lipids is poorly understood and, indeed, high lipid content is not a defining feature of most tumors. Nonetheless, the link between lipid metabolism and macrophage-driven inflammation in cancer warrants investigation, especially because atherosclerotic lesions may be ubiquitous in humans, appearing as fatty streaks in childhood and adolescence [31].

Nevertheless, the findings raised here are not without precedent in the cancer literature. Recent work has shown, for example, that dendritic cells with high lipid content are less effective at presenting tumor-associated antigens because of a defect in antigen processing [32] and several studies have supported a role for nuclear receptors [33] and the NLRP3 inflammasome [34-36] in cancer progression. Many questions remain. What is the role of the cholesterol efflux pathways in the macrophage cancer response? Do lipid-loaded monocytes/macrophages traffic to tumor sites and influence cancer progression? Is atherosclerosis-associated leukocytosis a major mechanism by which myeloid-derived suppressor cells (MDSC, see below) arise? Harnessing some of these atherosclerosis-related studies to better understand how metabolism and inflammation converge in cancer may provide unexpected insights and strengthen common threads between these two pathologies.

Can we learn from research studies on cancer to understand cardiovascular diseases better?

Ly-6C^high CCR2^high (but not Ly-6C^low CCR2⁻) mouse monocytes represent a sizeable fraction of a heterogeneous population of cells called Gr-1⁺ CD11b⁺ myeloid-derived suppressor cells (MDSCs), which are defined operationally by their capacity to regulate T-cell responses [37]. MDSCs are widely talked about in the context of cancer and have been also shown to control immune responses during pathogen infection, transplantation and trauma. Whether they participate during atherosclerosis remains largely unknown.

MDSCs produce immunosuppressive factors such as nitric oxide and reactive oxygen species that suppress anti-tumor effector T cell activity [38], enhance regulatory T cell responses [39] and collectively support tumor progression. Accumulating evidence also supports a key role for T cells in atherosclerosis [6]. In this context, however, effector T cells exert proatherogenic effects, whereas regulatory T cells dampen inflammation and are antiatherogenic. Consequently, when merely considering their impact on T cells, Ly-6C^high monocytes/MDSCs might exert antiatherogenic functions. This notion is unexplored because Ly-6C^high monocytes are well-known precursors of macrophages and lipid-rich foam cells in atheromata. Future studies should define the spectrum of MDSC-mediated functions (beside modulation of T cell responses) and the relative importance of these activities in distinct disease settings.

MDSCs (and TAM) also often activate STAT3 upon recruitment to tumors. The transcription factor, by triggering the NF-kB and JAK pathways, typically activates the production of enzymes (metalloproteinases), cytokines (IL-6, IL-10, IL-17, IL-23) and growth factors (VEGF, FGF) that elicit and sustain angiogenic and metastatic programs [40, 41]. Thus, STAT3 represents a master regulator of cancer-associated inflammation. Its role in atherosclerosis is essentially unaddressed.

MDSCs and their monocyte components often expand in humans and mice with cancer or other chronic inflammatory conditions [42-44]. The tumor-induced mechanisms that drive this expansion need further investigation, yet interesting studies already indicate that growth factors produced by tumor cells are important. As discussed above, experimental atherosclerosis also greatly expands Ly-6C^high monocytes in the host [19] and leukocytosis is a risk factor for cardiovascular disease in humans [45]. These findings indicate that both diseases trigger systemic monocyte responses, but they also prompt a number of questions: Does atherosclerosis elicit the production of bona-fide MDSCs? Which factors drive the Ly-6C^high monocyte/MDSC response in atherosclerosis and do these factors overlap with those involved in cancer? How do Ly-6C^high monocytes/MDSCs produced in cancer and atherosclerosis compare qualitatively? We propose that investigations of MDSC-like responses at the cellular and molecular levels in atherosclerosis will be valuable.

Conclusions

The growth of a tumor and an atherosclerotic lesion are two phenomena where monocyte accumulation and chronic inflammation converge. We focused on recent observations in atherosclerosis and cancer, but many insights from those studies will be broadly applicable. The observations, together with many others not discussed here, may serve as useful ‘think tanks’ for defining future experimental research and for understanding the two diseases better.