Similarly, chemo- or radiation therapy not only affects tumor cells, but also cells in the tumor microenvironment such as immune cells therefore, a higher apoptosis sensitivity of anti-tumor immune cells compared to cancer epithelial cells may be detrimental to patients. Such resistant cell populations could give rise to more aggressive tumors on recurrence. It is feasible that some tumors are more resistant to therapy than others by harboring resistant sub-populations, which is in line with evidence indicating the role of tumor heterogeneity in determining clinical outcome and responses to therapy.
Notwithstanding the successful application of these techniques in predicting chemotherapy responses and clinical outcome in cancer patients, these “bulk” techniques require a tissue homogenate to be analyzed and come with loss of important spatial information including the precise cell-of-origin of the signals. Both models have been validated experimentally in colon and other cancer cells. DR_MOMP models the BCL2 signaling network triggered upon activation of BH3-only proteins, and APOPTO-CELL models the activation of caspase-3 downstream of mitochondrial outer membrane permeabilization (MOMP). The ordinary differential equation-based models DR_MOMP and APOPTO-CELL calculate a cell’s sensitivity to induce apoptosis as a two-step process with little feed-back from one to the other process. Other groups, including our own, have used gene expression or protein level (western blotting and reverse protein phase array) data of apoptosis-regulating genes from fresh-frozen or formalin-fixed tissues as input into deterministic signaling network models to estimate the intrinsic apoptosis sensitivity of individual tumors.
BH3-peptide profiling has been successfully applied to predict outcome and responses to cancer therapeutics in solid cancers however, this technique requires fresh tissue. Predictions of individual patient’s apoptosis susceptibility are complicated by the signaling redundancies in key apoptosis pathways, as exemplified in the mitochondrial apoptosis pathway. Alterations in apoptosis signaling is key step in tumorigenesis and previous quantitative studies in solid tumor tissues found significant, but often complex differences in levels of individual anti- or pro-apoptotic proteins between different patients.
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