This proposal is aimed at answering how the level, type or duration of physical activity can influence cancer progression and prognosis. The long known biological effects of strenuous physical activity are increased cardiac output and increase in body temperature induced redirection blood flow towards the skin. There is little information in the literature on the effect of physical activity on tumor perfusion. During the past three decades a paradigm in tumor therapy has been to reduce tumor blood flow by anti-angiogenic and/or anti-vascular agents - this proposal suggests a novel shift in that paradigm. It is proposed that improved tumor control and prognosis could be achieved by increasing tumor blood flow. It is paradoxical that high angiogenic activity in tumors often does not result in well perfused or normoxic tumors. Vascular dysfunction in tumors, including leakiness, loss of hierarchical architecture, tortuosity, sluggish and inadequate blood flow and the lack of pericyte and smooth muscle cell coverage result in hypoxia and high interstitial fluid pressures (IFP), both of which are known negative prognostic indicators for disease free survival. Hypoxia is a key regulatory factor in proliferation of both cancer cells and cancer stem cell, and also plays a role in epithelal to mesenchymal transition (EMT) that result in cancer cell invasion and metastasis. Studies on mild systemic heating of tumor bearing mice have shown that increasing the body temperature by two degrees increases the number of perfused vessels and blood flow in tumors, and decreases IFP and hypoxia in the tumors. Drawing a parallel between mild systemic heating and physical activity induced increase in body temperature and cardiac output, it is expected that physical activity/exercise would increase tumor perfusion. The overall hypothesis is that physical activity, dependent upon the level, type, and duration can increase tumor blood flow and vascular normalization resulting in retardation of cancer progression and metastasis. The rationale being that the increased blood flow in tumors will result in: (1) reduced hypoxia and IFP; (2) increased fluid shear stress on vascular endothelial cells, leading to the secretion of specific growth factors and cytokines needed for recruitment of pericytes and vascular smooth muscle cells to tumor vessels resulting in vascular normalization. Normalization of tumor vessels would result in improved vascular function, low IFP and reduced hypoxia in tumors and consequently retardation of tumor growth and progression into metastasis.
Two specific aims are proposed:
Aim 1 - Measure tumor blood flow and secretion of growth factors and cytokines in tumors of mice under defined physical activity, both voluntary (exercise wheel) and forced (treadmill) at different levels and for different durations. Determine the ratio of mural cells to endothelial cells as a measure of vascular normalization.
Aim 2 - Determine whether physical activity/exercise-induced increase in blood flow in murine tumor models reduces tumor IFP and hypoxia, and improves cancer prognosis by slowing tumor growth and by reducing metastasis. Sedentary tumor bearing mice will be used as controls for all in vivo experiments.
This proposal is aimed at determining beneficial effects of physical activity in controlling cancer progression. Strenuous physical activity is known to increase body temperature and heart rate and the two together may increase blood flow in tumors. Increases in tumor blood flow will likely increase oxygen supply to the tumor tissue, reduce the negative effects of low oxygen in tumors, and thereby improve cancer control.
