Introduction to the Tumor-Host Interactions
Tumors are surrounded by resident non-cancerous cells, connective tissue, and extracellular matrix. These components are known as the tumor stroma or microenvironment. Within the past several years, it has become evident that the tumor microenvironment plays an important role in both tumor initiation and progression. Due to this new knowledge, researchers have begun to investigate treatments that target both the cancer and its surroundings.
Overview of the Tumor Microenvironment
Tumors are complex structures containing many different kinds of cells. For many years scientists focused their research on understanding thetransformation of normal cells to into neoplastic, or cancer, cells but spent little time studying other cells present within a tumor. However, within the past several years, it has become evident that other components of tumors, including resident non-cancerous cells (fibroblasts, endothelial cells), connective tissue, and extracellular matrix (ECM; components of tissues that provide structural support, such as proteins like collagen) are equally important both in tumor initiation (early development) and progression. Collectively, these components are known as the stroma. Many researchers prefer a broader term, the tumor microenvironment, instead of the stroma, as it encompasses infiltrating cells of the immune system (macrophages, lymphocytes) and cell free molecules (growth factors, proteases), in addition to the more or less permanent stromal components(1) As the role of the tumor environment in cancer has become better understood, researchers are hopeful that novel therapeutic agents can be developed that target not just cancer cells, but the environment around them. Drugs targeting both cancer cells and stromal components may be significantly more effective than those directed solely against cancer cells.
The components of the tumor microenvironment can be grouped into four categories: (1) cancer cells, (2) non-cancer cells, (3) secreted soluble factors, (4) and non-cellular solid material such as the ECM (2). The actual composition of the tumor microenvironment is highly variable, with differences seen between patients and often in different areas of the same tumor. The tumor microenvironment is often altered as the disease progresses; even the percentage of a tumor made up of cancer cells may change (3)
Communication between a tumor and its surroundings is very important. Both pro- and anti-tumor interactions occur that act to enhance or block tumor formation/progression. For example, one critical molecule, transforming growth factor beta (TGF-Β), is a critical regulator of tumor progression. TGF-Β is a potent inhibitor of cell growth and is secreted by multiple cell types within the tumor microenvironment; however, mutations in many advanced carcinomas result in cancer cells that are unaffected by TGF-Β (meaning they continue to grow even in the presence of TGF-Β). In addition, tumors themselves often secrete TGF-Β, which reduces the growth of surrounding normal cells, thus allowing the tumor cells to reproduce rapidly without competition from neighboring cells (1) In this way, tumors continue to grow at the expense of surrounding cells.
A Closer Look at The Stroma and Tumor Development
To examine the effect of the environment on tumor growth, rats were treated with a carcinogen to cause mutations. They were then given a drug to inhibit the growth of normal liver cells. Under these conditions, the only cells able to grow were those with mutations that allowed them to avoid the growth inhibitory effect of the drug (i.e. cancer cells). In rats given the carcinogen but not the growth inhibitor, no such cancer cells developed. This experiment demonstrated that tumors cannot grow when the surrounding tissue is normal; in other words, growth of a tumor from a single mutated cell can only occur when the stromal environment is altered in such a way to allow unrestrained tumor growth(4)
Conditions within the Tumor Microenvironment
The conditions within the tumor microenvironment differ considerably from those in normal tissue. Hypoxia (low oxygen levels), low pH (acidic conditions), and low glucose levels are common. In addition, massive cell death occurs, resulting in the release of proteins and other molecules into the surrounding environment. These factors may help or hurt tumor growth (1) Hypoxia results in the generation of oxygen free radicals which lead to DNA damage (mutation). Mechanisms for repairing this damage are also less efficient under hypoxic conditions. The end result is an increase in the mutation rate and greater variation within the tumor population. Another result is that only those cells with mutations that allow them to survive in harsh conditions will continue to grow and contribute to the tumor (2)
Importantly, the conditions within the tumor microenvironment do not affect cancer cells only. The normal cells surrounding a tumor exhibit altered characteristics compared to corresponding cells in normal tissue. These cells also develop mutations, and the tissue is often disorganized compared to normal tissue (3) These abnormal properties might arise in two ways. The conditions of the tumor microenvironment (hypoxia and low pH) may induce mutations, or soluble products (growth factors, cytokines) released from the tumor may alter the genes expressed by stromal cells (1) Interestingly, mutations have been identified in the stroma of non-cancerous tissue collected from breast cancer patients, suggesting that pre-existing genetic alterations in the stroma may provide the foundation for tumor initiation (2)Experiments have illustrated the importance of the stroma in tumor development.
A Closer Look at Tumor: Stroma Interactions
The influence of the tissues surrounding a tumor has been recognized for many years. In 1976, to examine the effect of the environment on tumor growth, rats were treated with a carcinogen to cause mutations. They were then given a drug to inhibit the growth of normal liver cells and part of the liver was removed to provide a strong growth stimulus. Under these conditions, the only cells able to grow were those with mutations that allowed them to avoid the growth inhibitory effect of the drug (i.e. cancer cells). In rats given the carcinogen but not the growth inhibitor, no tumors developed. This experiment suggested that tumors cannot grow when the surrounding tissue is normal; in other words, growth of a tumor from a single mutated cell can only occur when the stromal environment is altered in such a way to allow unrestrained tumor growth.(4)
Inflammatory Cells and Cancer
The role of the immune system in cancer is a double-edged sword. While there is evidence that it can be beneficial (for example, immunosuppressed patients, or those with weak immune systems, have a higher incidence of cancer), in many cases the immune system clearly promotes tumor growth (1) The role of immune cells in cancer is well documented. Innate immune cells (cells such as macrophages that do not produce antibodies but are capable of ingesting foreign organisms) are prominent in pre-malignant and malignant tissues, and are believed to contribute to tumor formation through the release of molecules that regulate cell growth and migration, alterations of the ECM, andangiogenesis (2) In addition, many cancers (gastric, cervical, colon, liver) are associated with infection and correlate with the activity of the normal host immune response. Chronic inflammatory conditions make people more likely to develop certain cancers; for example, patients with Crohn's disease have a higher incidence of colorectal cancer. A greater understanding of the ways by which the inflammatory response initiates cancer may lead to potent new cancer treatments (1)
In other cases the tumor itself attracts immune cells which can then impact tumor progression. Tumor cell damage and hypoxia attract macrophages from the blood into the tissue surrounding a tumor. In most cases, high tumor associated macrophage (TAM) counts are correlated with reduced survival. Many tumors secrete factors that prevent macrophages from alerting other immune cells to the presence of cancer cells, resulting in an inability of the immune system to recognize the tumor. Macrophages themselves secrete factors that enhance tumor cellproliferation, invasion, and promote angiogenesis. In addition, TAMs release oxygen free radicals and other mutagenic compounds that may create mutations in surrounding cells. The ability of TAMs to stick to tumor cells allows macrophages to carry tumor cells into the circulation and thus aid in the spread of the cancer (metastasis) (3) (4) (2)
Fibroblasts and Cancer
Fibroblasts are the predominant cells in the stroma. They are responsible for generating the ECM as well as connective tissue. Because each tissue has different requirements, fibroblasts from different organs express different genes. Changes in fibroblast behaviors are associated with tumor progression, mostly due to factors made by the tumor. Fibroblasts begin to express α-SMA (alpha-smooth muscle actin), which allows them to contract. These myofibroblasts are highly proliferative and are surrounded by a dense meshwork of the structural protein collagen. This profile is known as desmoplasia and is often associated with recruitment of immune cells and angiogenesis (1) (2)
Interestingly, although the behavior (phenotype) of fibroblasts is often altered by close proximity to a tumor, in other cases altered fibroblasts have been isolated from patients with no cancer, but who have hereditary predispositions to the disease. This observation suggests that these altered fibroblasts may actually aid in the development of cancer(3) How might these cells become oncogenic in the absence of a tumor? Several possibilities exist, including exposure to carcinogens, accumulation of genetic damage due to aging, and hormone imbalances. Molecules present in healing wounds can also alter fibroblasts in such a way that they resemble fibroblasts found near tumors(2)
Matrix Metalloproteinases and Cancer
One of the most critical roles performed by fibroblasts, both in normal and cancer tissue, is the production and remodeling of the extracellular matrix (ECM). Not only does the ECM impart structural support and strength to tissues, it also provides attachment sites for cell surface receptors, and functions as a reservoir of cytokines and other growth factors(1) The structure of tumor-associated ECM is abnormal, with loose structure and disorganized collagen fibers(2) Matrix metalloproteinases (MMPs) are a large family of enzymes capable of degrading components of the ECM and are critical in maintenance of the ECM. Degradation of the ECM by MMPs releases growth factors, enhances migration, and alters cell:cell and cell:ECM interactions(3). Although MMPs can be produced by tumor cells, most are produced by fibroblasts and macrophages, and high levels of MMPs are found at the tumor:stroma interface(4). Because MMPs are secreted into the surrounding environment by these cells, they are a good example of the interaction that occurs between a tumor and its environment.
Evidence indicates that MMPs are key players in multiple steps of tumor progression; they promote metastasis, angiogenesis, and even tumor initiation. One of the many paradoxes of MMP activity is that MMPs often have opposing effects depending on the composition of the tumor environment and the nature of MMPs present. For example, MMPs can either promote or inhibit angiogenesis, depending on the molecules they release from the ECM(5) <(3) Because of their potent effects on tumor formation and metastasis, several clinical trials attempted to use MMP inhibitors as anticancer therapy. However, these trials were soon stopped as patients developed muscle and bone pain, formed connective tissue nodules, and developed joint disorders. These trials highlight the difficulty of targeting molecules critical for the function of multiple tissues(5).
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