MBI Emphasis Year on Cancer and Its Environment 2014-2015
Cancer is one of the world's biggest killers. Cancer is initiated from cells with specific genetic mutations that cause them to lose control of proliferation. This loss of proliferative control, whilst necessary, is not sufficient to cause cancer; subsequent mutations and selection need to occur. Cancer is an evolutionary disease, where rounds of mutation and selection will drive the emergence of a tumor. The selection pressures that a growing tumor encounters are manifold but can largely be classified as microenvironmental. The tumor microenvironment consists of the extracellular matrix, growth promoting and inhibiting factors, nutrients (including oxygen and glucose), chemokines, and importantly, other cell types including (but not limited to) fibroblasts, immune cells, endothelial cells and normal epithelial cells. In order for selection to operate properly there needs to be variation in the tumor population -- tumors are known to be genetically extremely heterogeneous. This genetic heterogeneity produces phenotypic heterogeneity in which individual tumor cells can have distinct phenotypic behaviors within the same tumor.
As the tumor mass grows, so does the heterogeneity; eventually the mass becomes too large to be supported by nutrient diffusion alone, so some subset of the tumor population then becomes hypoxic. This hypoxia will eventually give way to cell death if nutrient levels continue to fall but the tumor has two ways to combat this problem. First it can begin to utilize a different nutrient source (e.g. glucose) by altering its metabolism and second it can initiate the process of angiogenesis from nearby vessels. The process of recruiting and growing a new vasculature, once fully realized, gives the tumor an almost limitless nutrient source and also a highway to other parts of the human body. Metastases are cells that successfully break away from the primary tumor and initiate new tumors at secondary sites. There can be many of these metastatic cancers at many different sites in the body and ultimately, for most patients, it is these cancers that cause death.
There are hundreds of types of cancer, classified by the tissue from which they arise and by the type of cells involved. For example, leukemia is a cancer of white blood cells, carcinoma is a cancer originating from epithelial cells and glioma is cancer of the brain. There are also many ways to treat cancer, most of which start with surgery and end with chemotherapy and/or radiotherapy. In recent years we have seen the emergence of immunotherapies and molecularly targeted therapies. Immunotherapies exploit the immune system by either enriching or aiding its ability to attack the cancer. Molecularly targeted therapies exploit the fact that specific mutations are present in a large proportion of the cancer cells and block the activity of these mutations. Both of these new therapies have had differing degrees of success but, as in most treatments, failure is ultimately caused by the emergence of a resistant tumor population that tends to be more aggressive and less easy to treat.
This brief overview illustrates the complex interactions at the molecular, cellular and tissue levels involved in the emergence and development of cancer, and emphasizes the need for mathematical models that synthesize a framework for understanding the existing phenomena and that make testable predictions as to how interventions will influence the outcome.