In our previous P01 project we examined the relationship between the expression of CXCR4 by metastatic prostate cancers (PCa) and their bone homing behavior. From these studies we acquired data that suggest that not only do PCa's use the CXCR4/SDF-1 pathway to home to bone - but there is a strong likelihood they use the hematopoietic stem cell (HSC) 'niche' itself to colonize the skeleton. Here our work in this field has demonstrated that annexin II (Anxa2) expressed by osteoblasts (08s) and plays a critical role in niche selection. Among the most compelling mechanisms to account for these observations are either that (i) Anxa2 acts as an adhesion ligand, and (ii) when HSCs bind to Anxa2, quiescence is induced. Our preliminary data strongly suggests that similar molecular mechanisms are functional in metastatic PCa in the marrow. Hypothesis: Metastatic pea parasitizes the 'niche' as a molecular mechanism for osteotropism. The following aims are proposed: (1) Define the location of the metastatic 'niche' and its interactions with primary tumors. Sub hypothesis: Molecular cross talk between a primary (1 ) tumor and the premetastatic 'niche' helps to govern the homing of metastatic PCa. We will explore the localization of PCa metastatic niche in bone. We will determine where PCa cells injected by an (i) i.c. route localize in marrow and (ii) whether the same niche is seeded by tumors established in our orthotopic metastasis model. (iii) Determine if the expression of CXCR4/RDC1 and Anxa2r is different when PCa cells are in the 'niche'. (2) Determine whether expression of SDF-1 and Anxa2 by the 'niche' is essential for metastasis. Sub hypothesis: Co-opting the HSC niche is essential for metastasis. In this aim we will determine if the expression of (2A) SDF-1, (28) Anxa2 are essential for homing/lodging of PCa in bone. PCa cells are implanted in vivo orthotopically and 'shed' or disseminated cells are tracked by QPCR. This assay allows us to identify and explore extremely early events. (3) Define the interaction(s) of PCa and the 'niche'. Sub hypothesis: PCa use the HSC niche to establish a 'foot hold' in the marrow. We will; (3A) define the role that SDF-1 signaling pathways, (38) Anxa2 and its receptor (Anxa2r) playas molecular mechanisms for 'niche' parasitism once metastatic PCa cells have entered the niche. In our final sub aim, we will link the previous studies to (3C) determine if Anxa2/Anxa2r signaling facilitates PCa growth in bone via SDF-1.
Growth of prostate cancer in the bone is a common and serious late event of prostate cancer. Our proposed work will help define why prostate cancer can thrive in the bone including identifying key signals used for the establishment of prostate cancer metastases in bone. This work will help lay the foundations for evaluating therapeutic interventions.
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