Interdisciplinary Study of Acid-Meditated Tumor Invasion

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DESCRIPTION (provided by applicant): The proposed study investigates a novel, conceptually simple mechanism for cancer invasion developed by the investigators. Its goal is a fuller understanding of the structure and dynamics of the tumor-host interface through an interdisciplinary approach with continuous interaction between laboratory experiments and the formulation and analysis of mathematical models. This work was initiated by extensive evidence that tumor metabolism is consistently different from normal tissue with increased reliance on glycolytic pathways for energy production. The investigators hypothesized that excess H+ ions excreted by tumor cells would diffuse into the tumor-host interface and adjacent normal tissue creating an acidic microenvironment favorable for tumor invasion because: 1. Normal cells are significantly less tolerant to acidic pile than are tumor cells 2.acidic pHe promotes release of proteolytic enzymes breaking down extracellular matrix facilitating tumor invasion 3. acid pHe increases release of IL8 and VEGF promoting angiogenesis. This hypothesis is formalized through mathematical models using both coupled partial differential equations and a modified cellular automata approach. Critical parameter values in these models such as H+ production and diffusion coefficient have been determine experimentally. This has allowed the mathematical models to produce detailed predictions of the peritumoral acid gradient and the resulting morphology of the tumor-host interface. These predictions have been investigated using a dorsal skin fold chamber technique. Preliminary data measuring pHe using fluorescence ratio imaging (FRIM) has confirmed a gradient of H+ ions extending from the tumor edge into adjacent normal tissue. Using dye exclusion techniques loss of viability has been demonstrated in peritumoral normal cells exposed to the acidic environment - a key component of the hypothesis. The proposed study will extend the experimental observations by comparing the peritumoral pHe gradients and the resulting changes in the peritumoral normal tissue and tumor growth dynamics in the MCF7/s and MDA-mb-435 tumor lines which have markedly different acid production rates and in-vivo behavior. The mathematical models will be further refined as additional parameter values can be determined. Perturbations that produce slowing or reversal of the traveling wave solution to the state equations (ie tumor growth) will be explored to predict possible new treatment strategies.