Inflammation and Cancer

Introduction

Adult tissues contain a multitude of cell types that are spatially and functionally coordinated to regulate normal tissue homeostasis. When a tissue becomes injured, for example, from a skin wound, there is a surge of infiltrating cell types and inflammatory responses within the microenvironment that work in concert to heal the injury and restore tissue homeostasis. Interestingly, tumors share many features with injured tissue, as their microenvironment is characterized by various infiltrating immune cell types and chronic inflammation. However, in cancer, the coordinated cell-cell interactions that are critical during normal tissue homeostasis are disrupted, as the tumor acquires the capacity to chronically circumvent normalizing cues from the microenvironment, and in turn, the microenvironment evolves to accommodate the growing tumor. In this chapter, we discuss representative examples of the positive and negative roles that different types of immune cells can play in cancer, to underscore the importance of inflammation in regulating the initiation and progression of this disease. We review the multifaceted role of inflammation in cancer, with a focus on hematopoiesis, chronic injury and tumorigenesis, and the contributions of myeloid and lymphoid cell types to a growing tumor.

Hematopoiesis and the Immune System

Hematopoiesis is the process by which hematopoietic progenitor cells (HPCs) from the bone marrow constitute all mature cell types in the blood ( Figure 19-1 ). As progenitor cells, HPCs have the capacity to either self-renew or differentiate into either myeloid or lymphoid lineages, to ensure that both immature and mature components of the blood system are not depleted. The myeloid lineage of HPC differentiation gives rise to thrombocytes, erythrocytes, mast cells, granulocytes, and monocytes, which further differentiate into macrophages and myeloid dendritic cells. In contrast, the lymphoid lineage of HPC differentiation gives rise to lymphoblasts, which undergo lymphopoiesis to generate B cells, T cells, and natural killer (NK) cells.

There are two arms of the immune system that use cells generated through hematopoiesis to mediate immunogenic functions: the innate and adaptive arms. The innate immune system provides immediate chemical and cellular responses to foreign microorganisms that invade the body. Chemical defenses, including the complement system, consist of biochemical cascades that attack invading cells, via the exponential activation and release of proteases. Cellular defenses are largely mediated by NK and myeloid cell types, including macrophages, dendritic cells (DCs), mast cells, and granulocytes. These cells work together to phagocytose or ingest invading microorganisms, including bacteria and viruses, or to present antigens for recognition by cells of the adaptive immune system. Of note, the adaptive arm of the immune system is largely mediated by lymphoid cell types. Examples include T cells, which recognize antigens presented by major histocompatibility complex (MHC) molecules, and B cells, which recognize antigens in their native form. Whereas the innate immune system provides an immediate defense mechanism against foreign invaders, the adaptive immune system ensures that the body remembers how to protect itself against specific microorganisms in the future.

Chronic Inflammation and Tumor Incidence

The link between chronic inflammation and tumorigenesis was first proposed by Rudolf Virchow in 1863 after he made a seminal observation that linked the presence of infiltrating leukocytes with cancer. Perhaps one of the most straightforward pieces of evidence that deregulated inflammation affects tumorigenesis is that tissues which experience chronic injury exhibit a high risk for subsequently developing tumors. Classic examples of tissue damage leading to chronic inflammation include the development of lung cancer arising from tobacco smoke, or skin cancer resulting from exposure to UV (ultraviolet) light ( Table 19-1 ). In both of these cases, the onset of tumorigenesis is supported by a repetitive inflammatory response, whereby immune cells accumulate and their tissue-repair functions become excessive and maladaptive, leading to the development of a pro-tumorigenic niche. Recruited inflammatory cells support disease progression by providing critical growth factors and cytokines to sustain tumorigenesis.

Another piece of evidence that deregulated inflammation contributes to tumorigenesis is the correlation between chronic viral infection and cancer initiation. In 1911, the discovery of a tumor virus in chickens by Peyton Rous, later termed the Rous sarcoma virus (RSV), was a pivotal discovery in molecular cancer biology that led to the discovery of src , the first oncogene. Decades later, Bissell and colleagues demonstrated a clear connection between inflammation and tumorigenesis, when they showed that chickens systemically infected with RSV only developed tumors at the site of initial injection or a subsequent inflicted wound. It is also known that people infected with hepatitis B or C virus are prone to developing cirrhosis of the liver, which increases the risk of hepatocellular carcinoma by 100-fold. In fact, it has recently been estimated that approximately 2 million cancer cases worldwide, representing 16% of total cases, are caused by infectious agents every year. For a list of infectious agents, inflammatory conditions, and associated cancers, refer to Table 19-1 .

Recent attempts to understand the connection between infection, inflammation, and cancer have led to the Human Microbiome Project, which was initiated by the National Institutes of Health (NIH) Roadmap for Medical Research. The project was launched in an effort to gain insight into how microorganisms influence health and disease, given that the human body contains 10 times more microbial cells than human cells, and 100 times more microbial genes (i.e., the microbiome) than human genes. Indeed, it is estimated that in humans, the distal gut contains up to 1000 species and 7000 strains of microbes. It is currently known that microorganisms contribute to the development of diseases including cancer, despite often maintaining symbiotic relationships with the human body. For example, it has been shown that stomach cancer can arise from chronic gastric inflammation caused by Helicobacter pylori infection. Inflammatory bowel disease, comprising ulcerative colitis and Crohn’s disease, is also associated with recurrent bacterial infection and can predispose to colorectal cancer. However, the specific mechanisms and intercellular interactions that disrupt microbial homeostasis, leading to inflammation-induced cancer, remain elusive and an area of active investigation.

Inflammation and the Metastatic Cascade

In each of the cases just described, the onset of tumorigenesis is supported by an unresolved inflammatory response that contributes to a pro-tumorigenic niche, characterized by a plethora of different stromal cell types, growth factors, and cytokines ( Figure 19-2 ). For example, studies in breast cancer have shown that the type of inflammatory response is an important predictor of tumor development. In particular, acute inflammation involving cytolytic CD8 ⁺ T lymphocytes, CD4 ⁺ T helper (T _H 1) cells, or classically activated M1 macrophages is generally anti-tumorigenic, whereas chronic inflammation involving B lymphocytes, CD4 ⁺ T helper (T _H 2) cells, or alternatively activated M2 macrophages is frequently pro-tumorigenic ( Table 19-2 ). These findings demonstrate a complex relationship between tumor cells and their microenvironment and suggest that the development of a pro-tumorigenic niche is highly dependent on the type of immune response that ensues.

The metastatic cascade begins at the primary tumor site, when tumor cells recruit a vascular supply (angiogenesis), invade through the extracellular matrix (ECM), intravasate into the circulation, disseminate through the body, extravasate at secondary sites, and self-renew to sustain secondary tumor growth. Bone marrow–derived cells have diverse effects on each step of the metastatic cascade and render the microenvironment susceptible or resistant to tumorigenic growth. For example, studies in breast cancer have shown that tumor-associated macrophages (TAMs) are critical for promoting angiogenesis and tumor cell invasion and helping cancer cells to cross blood vessel walls. Within the circulation, platelets can enhance the survival of tumor cells by protecting them from NK cell-mediated death and promoting their adhesion to the endothelium at the site of metastasis. Furthermore, myeloid-derived suppressor cells play a role in suppressing immune surveillance of cancer cells, promoting tumor growth. In an elegant study by Lyden and colleagues, hematopoietic progenitor cells (HPCs) positive for vascular endothelial growth factor receptor 1 (VEGFR1) and endothelial progenitor cells positive for VEGFR2 were both shown to be required for mediating neovascularization at sites of future metastasis: the premetastatic niche. Another study reported that recruited CD11c ⁺ DC precursors were capable of assembling tumor-associated neovessels in a model of ovarian carcinoma. As illustrated by these examples, the diverse effects of all these different immune cell types during multiple steps of the metastatic cascade underscore the complexity of tumor-microenvironment relationships in cancer. In the following section, various immune cell types and their roles during tumorigenesis and metastasis are reviewed.

Immune Cells in Cancer

Myeloid Lineage

Macrophages

In normal physiological contexts, macrophages defend against infection, clear debris, and remodel injured tissue to maintain homeostasis. In cancer, normal macrophage function is hijacked by tumor cells to support tumor progression. In fact, in 80% of epithelial cancers, it has been shown that high macrophage infiltration is associated with poor patient prognosis. TAMs typically represent the major immune cell type infiltrating tumors, and in some cancers, such as gliomas and breast cancer, TAMs can constitute up to 30% of the total tumor mass. TAM progenitors are largely recruited from the bone marrow and, once in the tumor mass, represent a critical source of secreted growth factors, proteases, and cytokines that participate in paracrine signaling loops with tumor cells to support invasive phenotypes. One important function of TAMs is that they help tumor cells enter blood vessels, a process called intravasation. Condeelis and colleagues have published seminal studies using sophisticated multiphoton intravital imaging techniques to observe intimate macrophage–tumor cell interactions during metastatic dissemination in live animals. These studies have shown that macrophages are primarily localized in perivascular areas, where they help tumor cells intravasate into the circulation ( Figure 19-3 ).

One explanation for the divergent functions of macrophages during normal tissue homeostasis versus tumorigenesis lies in their polarization state. Macrophages are phenotypically plastic. They can alter their polarization status to rapidly accommodate for the needs of different physiological contexts. At the extremes of their phenotypic continuum, macrophages range from M1 to M2 polarization states. “Classically activated” (M1-polarized) macrophages produce type I pro-inflammatory cytokines and participate in antigen presentation, and they play an anti-tumorigenic role in cancer. On the other hand, “alternatively activated” (M2-polarized) macrophages produce type II cytokines and anti-inflammatory responses, and they play a pro-tumorigenic role in cancer ( Figure 19-4 ). Of note, M2-polarized TAMs have been shown to promote tumorigenesis by providing a major source of proteases and chemokines that support tumor invasion and therapeutic resistance in multiple cancer types. For example, it has been shown that TAM-derived cathepsin proteases B and S promote breast cancer growth and metastasis by blunting chemotherapy-induced apoptosis. Furthermore, tumor-secreted cytokines, such as interleukin-4 (IL-4), hijack macrophages in the tumor niche, activating them toward a pro-tumorigenic state. Additional characterization of bidirectional interactions between tumor cells and TAMs will likely provide valuable information about how to manipulate the tumor niche in a therapeutic context.

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