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Manipulating the tumor microenvironment to slow cancer growth

University of British Columbia

The tumor microenvironment encompasses all of the factors and accessory cells which interact with a tumor and, more often than not, are co-opted by tumor-secreted factors to help the cancer grow. In this thesis, we examined elements of the tumor microenvironment, specifically the cancer-promoting M2 macrophages (MΦs) and tumor glucose supply and metabolism. In the vast majority of advanced cancer patients and tumor-bearing animals, their tumors contain MΦs that are profoundly skewed to a cancer-promoting M2 phenotype, which often correlates with a poor prognosis. As well, these same tumor tissues are more dependent on high glucose levels for energy and survival than most normal tissues. Although MΦ phenotype and tumor cell glucose metabolism are quite disparate fields of study, we employed similar strategies to uncover what regulates them in order to explore mechanisms to reduce tumor growth. In our M2 MΦ studies, we assessed the phenotypic plasticity of mature IL-4-induced M2 MΦs and found their phenotype (i.e., cell-surface markers, cytokine secretion, and T cell stimulatory properties) could be fully reversed with IL-4 withdrawal and subsequent IFN-γ priming, demonstrating that M2 MΦs, indeed, can be reprogrammed even if they are phenotypically polarized. As well, we uncovered a circuit of M2-MΦ generation which may be relevant in vivo in the M2-skewed SHIP-/- mouse model. This circuit involves the sensitization of MΦs and MΦ progenitors, via IgG and TGF-β-containing mouse plasma, to low levels of constitutive IL-4 uniquely secreted by SHIP-/- basophils. In a similar vein, and based on the Warburg effect, which describes the propensity of cancer cells to consume glucose via glycolysis rather than oxidative phosphorylation (OXPHOS), we designed low carbohydrate (CHO) diets to limit the glucose supply to tumors. We found that mice fed our low CHO diets had lowered blood glucose, insulin, and lactate, and this correlated with a slower growth rate of implanted tumors, and a lower cancer incidence in a spontaneous mouse mammary carcinoma model. Furthermore, our diets worked additively with known anti-cancer agents (i.e.,Temsirolimus, Celebrex) to slow tumor growth.

Text

2012-04-26

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/42239

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/