Tumors are complex structures containing many different kinds of cells. For many years scientists focused their research on understanding the transformation 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).
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