The physical microenvironment in carcinogenesis
Project PI: Alexander Anderson, Ph.D.
The development of cancer (carcinogenesis) is a prolonged multi-step process with progression from normal through premalignant lesions (carcinoma in-situ) until an invasive cancer emerges often years or decades after the initiating even. This is commonly termed “somatic evolution” that is the result of a sequence of mutations in oncogenes and tumor suppressor genes. We have proposed that hypoxia and acidosis also play a critical role in carcinogenesis due to the previously unrecognized role of the anatomy and physiology of epithelial surfaces. In-situ tumor development occurs on the surface of the basement membrane which separates the proliferating cells from their blood supply. Stromal interactions (e.g. activated fibroblasts produce growth factors) also play an important role in both initiation and progression. As the tumor develops, diffusion of substrate and metabolites create regions of hypoxia and acidosis in the in-situ cancer. These harsh conditions in the physical microenvironment produce Darwinian selection forces that select for cells with upregulated glycolysis and resistance to acid-mediated cytotoxicity. We propose this creates a highly invasive phenotype that produces an acidic environment through constitutively upregulated glycolysis that is toxic to other cell populations but not to itself. Furthermore, we propose that this phenotype is necessary for transition from in-situ to invasive cancer thus explaining the ubiquitous presence of increased glucose uptake in invasive and metastatic cancers.