The Detection and Functional Contribution of ALCAM in Cancer Progression

Abstract

Cell adhesion molecules play a vital role in modulating both normal and tumor cell behavior. The focus of my research has been to investigate the contribution of Activated Leukocyte Cell Adhesion Molecule (ALCAM) to tumor progression. The functional contribution of ALCAM to metastasis was investigated using murine models of prostate cancer while a retrospective cohort of colorectal cancer patients was used to determine whether ALCAM has a clinical prognostic value in distinguishing aggressive cancer types. In addition to the function contribution and clinical relevance I searched for the modulatory cytokine responsible for promoting ALCAM ectodomain shedding via ADAM17. Our results, presented within this dissertation, explore the contribution of tumor-derived ALCAM in prostate tumorigenesis in vivo and the clinical application of intratumoral ALCAM shedding in colorectal cancer progression. We have now shown that the loss of tumor-specific ALCAM expression results in decreased metastasis to skeletal sites and reduced tumor cell survival in the bone microenvironment through enhanced apoptosis. In addition, we identified transforming growth factor beta-1 (TGFβ), a key tumor-associated cytokine in bone metastasis, as a major driver of ALCAM ectodomain shedding. In addition to enhanced ectodomain shedding and mRNA expression, ALCAM is required for the enhanced migratory behavior of tumor cells in response to TGFβ. Moreover, the development and application of a novel antibody specific to the intracellular domain of ALCAM has allowed for the investigation of intratumoral ALCAM shedding in retrospective clinical studies. Enhanced intratumoral ALCAM shedding in early colorectal disease, stage II specifically, is associated with decreased patient survival. In conclusion, we have been able to demonstrate that ALCAM shedding, driven by pro-tumorigenic cytokines, contributes to cancer metastasis and correlates clinically to poor patient outcome.