Our goal is to understand human prostate tumor cell adhesion, migration and to use this information to block subsequent aggressive spread to late stage secondary skeletal sites. Specifically, we will identify the role of laminin binding integrins A6B1, A6pB1 and A3B1 at the molecular and cellular level using both in vitro tissue culture and in vivo xenograft SCID mouse models. We will translate these findings to utilize blockers of integrin interactions and aggressive spread. Archived human prostate cancer bone metastases will validate key results. Several key observations have stimulated this work. First, laminin 511 binding integrins drive invasion and metastasis of human prostate cancer. They are persistently expressed in human prostate metastatic lesions, including bone. Recently, a laminin 511 receptor, A6 integrin, was 1 of 7 new prostate cancer susceptibility loci discovered in a genome-wide association study. Lastly, elevated expression of A6B1 is correlated with reduced patient survival in cancer. We and others have shown that blocking expression or function of A6B1 curtails invasion and metastasis of tumor cells both in vivo and in vitro. How they facilitate adhesion and migration, with subsequent metastasis and/or recurrent disease has yet to be fully elucidated. The central hypothesis is that laminin 511 adhesion and colonization of cancer cells in bone is dependent upon laminin binding integrins and regulated by novel pericellular proteolysis involving the uPA/uPAR axis. Early (and often clinically inapparent) bone metastasis can provide a sanctuary site for tumor cells. Deployment of tumor cells from bone via A6pB1 may explain the clinical reality of widespread skeletal recurrence as aggressive metastatic disease 5 to 10 years after primary therapy. If proven correct, this hypothesis could have important translational implications. The therapeutic strategy would consist of ablation of the primary lesion using radiotherapy and/or prostatectomy coupled with prophylactic anti-integrin antibodies or peptide combinations to eliminate osseous sanctuary sites, and thereby the potential source of late bone recurrence. This is a new concept of cancer control directed at adhesion dependent and bone resident cancer. We will test our central hypothesis by three specific aims using a combination of expertise including collaborations between experts in Molecular Cellular Biology, Pathology and Radiology.
All aims contain functional endpoints of laminin 511 dependent adhesion and migration using in vitro tissue culture methods and in vivo assays, using an intra- osseous injection xenograft model, digital radiographs and quantitative micro CT imaging. Understanding the fundamental molecular basis of adhesion dependent sanctuary of tumor cells in bone and their subsequent deployment will lend novel insight into mechanisms controlling cancer cell migration and metastasis to secondary skeletal sites. Metastasis to secondary sites is a cause of skeletal morbidity, disease progression, cancer pain or death. Recurrent disease could be potentially eliminated by adding important "pre-emptive" strategies to conventional therapy.
Our goal is to understand human prostate tumor cell adhesion, migration and to use this information to block subsequent aggressive spread to late stage secondary skeletal sites. Early (and often clinically not apparent) bone metastasis can provide a sanctuary site for tumor cells and result in widespread skeletal recurrence and pain as aggressive metastatic disease 5 to 10 years after primary therapy. If successful, the results of the project will provide a new therapeutic strategy and concept of cancer control directed at blocking the success of early adhesion dependent tumors and in particular painful bone resident cancer.
|Kacsinta, Apollo D; Rubenstein, Cynthia S; Sroka, Isis C et al. (2014) Intracellular modifiers of integrin alpha 6p production in aggressive prostate and breast cancer cell lines. Biochem Biophys Res Commun 454:335-40|
|Landowski, Terry H; Gard, Jaime; Pond, Erika et al. (2014) Targeting integrin ?6 stimulates curative-type bone metastasis lesions in a xenograft model. Mol Cancer Ther 13:1558-66|
|Nagle, Raymond B; Cress, Anne E (2011) Metastasis Update: Human Prostate Carcinoma Invasion via Tubulogenesis. Prostate Cancer 2011:249290|
|Sroka, Isis C; Sandoval, Cynthia P; Chopra, Harsharon et al. (2011) Macrophage-dependent cleavage of the laminin receptor ?6?1 in prostate cancer. Mol Cancer Res 9:1319-28|