Team:McMaster II/Tumor MicroEnvironment

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Mcmaster

Tumour Microenvironment


Tumour cell growth generates a complex physiological environment that is distinct from regions surrounding healthy tissues. This has been termed the tumour microenvironment (TME). The TME is well established to promote tumour proliferation, heterogeneity between cells within a tumour, and resistance to current chemotherapeutic agents. The TME is also capable of preventing the entry of cytotoxic T-cells, thereby decreasing the efficacy of immunotherapeutic options such as chimeric antigen T-cells. As a result, current treatment strategies are widely incapable of adjusting to the TME and ineffective at eliminating solid tumours without relapse (1-3).
As the rapid rate of tumour growth exceeds the capacity of the surrounding vasculature to grow and deliver adequate blood supply to the mass, the TME becomes distinguishably hypoxic (1,4). The hypoxic environment induces intracellular acidity through the Warburg Effect, in which cellular metabolism becomes predominantly anaerobic thus producing substantial amounts of lactic acid (5). Since a hypoxic environment is generally unfavourable for cell growth, the TME leads to downstream activation of Hypoxia Inducible Factor (HIF-1), which enables the proliferation only of cancer cells in the acidic environment, while healthy cells cannot survive. Although a certain heterogeneity in the composition of the TME does exist, fundamentally conserved characteristics include hypoxia and acidity (6). Both of these are factors that we are harnessing in our genetic circuit in order to develop a localized, tumour cell-specific killing agent.

  1. Ackerman D, Simon MC. Hypoxia, lipids, and cancer: surviving the harsh tumor microenvironment. Trends in cell biology. 2014 Aug 31;24(8):472-8.
  2. Vaupel P, Mayer A. Hypoxia in cancer: significance and impact on clinical outcome. Cancer and Metastasis Reviews. 2007 Jun 1;26(2):225-39.
  3. Subarsky P, Hill RP. The hypoxic tumour microenvironment and metastatic progression. Clinical and Experimental Metastasis. 2003 May 1;20(3):237-50.
  4. Cairns RA, Mak TW. The current state of cancer metabolism. Nature Reviews Cancer. 2016 Oct 1;16(10):613-4.
  5. Koppenol WH, Bounds PL, Dang CV. Otto Warburg's contributions to current concepts of cancer metabolism. Nature Reviews Cancer. 2011 May 1;11(5).
  6. Albini A, Sporn MB. The tumour microenvironment as a target for chemoprevention. Nature reviews. Cancer. 2007 Feb 1;7(2):139.