Mary Helen Barcellos-Hoff

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  Carcinogenesis in Context: Tumor Heterogeneity as a Function of Host Biology
  Mary Helen Barcellos-Hoff

  Both clinical and experimental data show that the stroma is highly involved in early malignancy, supporting the idea of reciprocal evolution of the malignant cell and the tumor microenvironment. Although it is clear that stroma composition and signaling is altered in cancer, less is known about how and when stroma contributes to carcinogenesis and how carcinogens, like radiation, might alter these processes. To investigate how tumor diversity evolves in the context of different physiological states (e.g. as a function of age and ionizing radiation exposure) we developed a mammary chimera model in which histologically and genomically diverse cancer originate from a p53 null epithelium orthotopically transplanted to a syngeneic wildtype host. We use expression profiling of tissue and tumors to identify the biological ‘bookends’, those processes initiated in normal tissue that appear to contribute to the development and are recapitulated in particular types of tumors. These studies show that the spectrum of mammary tumor types is strongly influenced by the host biology, opening new perspective on the drivers of aggressive cancer. The mounting evidence from these and other studies that cancer results from a systemic failure in which cells other than those with oncogenic alterations determine the frequency and type of clinical cancer is changing the cancer paradigm. To account for this, we propose that the tumor microenvironment is built through rate-limiting steps during multi-stage carcinogenesis [Barcellos-Hoff, 2013 #18417]. In this model, construction of a ‘pre-cancer niche’ is a necessary early step required for initiated cells to survive and evolve; subsequent niche expansion and maturation accompany promotion and progression respectively. The model postulates that cancer cell survival and proliferation is as much a function of the successful niche construction as it is of the natural selection for specific cancer cell mutations. Consequently, cancer represents an emergent property that requires a comprehensive analysis of the cell-cell interactions during the course of carcinogenesis. Moreover, in contrast to initiation, which is stochastic by nature, niche construction represents a robust target for native immunosuppression and a potent target for cancer prevention.