Heterogeneity in cancer is an observed fact, both genetically and phenotypically. Cell-cell variation is seen in almost all aspects of cancer from early development through to invasion and subsequent metastasis. Our current understanding of this heterogeneity has mainly focused at the genetic scale with little information on how this variation translates to actual changes in cell phenotypic behavior. Given that many genotypes can lead to the same cellular phenotype, we must also understand the range and scope of this heterogeneity at the phenotypic scale as ultimately this variability will dictate the aggressiveness of the tumor and its treatability. Central to our understanding of this heterogeneity is how the tumor cells interact with each other and with their microenvironment.
The tumor microenvironment is not simply the extra cellular matrix, but a complex milieu consisting of 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. These microenvironmental factors and different cell types interact with one another and the tumor as it grows. The role of endothelial cells and the immune system in cancer development are fairly well established, but less is known about the function of host fibroblasts in this process. Most solid tumors present as dense fibrotic masses, which suggests that fibroblasts contribute to tumor growth by infiltrating and depositing extracellular matrix proteins. In addition, the phenotype of fibroblasts found within and around tumors (activated fibroblasts or cancer associated fibroblasts: CAFs) is different to normal fibroblasts, and closely resembles myofibroblasts. Fibroblasts act in wound healing, angiogenesis and tissue remodeling by releasing growth factors and proteases such as matrix metalloproteinases. They also deposit matrix proteins such as laminin, tenascin and fibronectin. Therefore, if the growing tumor can co-opt such fibroblasts it has an unlimited source of many of the fundamental elements required for growth and invasion.
The two central themes of this workshop are:
Since a highly heterogeneous tumor has the potential to adapt to any microenvironment, understanding how interactions between the growing tumor and its microenvironment modulate tumor heterogeneity is critical to unraveling the mechanisms of cancer initiation.