The management of pain and morbidity due to the spreading and growth of cancer within bone remains to be a paramount problem in clinical care. Cancer cells actively transform bone, however, the molecular requirements and mechanisms of this process remain unclear. This study shows that functional modulation of the avb3 integrin receptor in prostate cancer cells is required for progression within bone and determines tumor-induced bone tissue transformation. Using histology and quantitative microCT analysis, we show that avb3 integrin is required not only for tumor growth within the bone but for tumor-induced bone gain, a response resembling bone lesions in prostate cancer patients. Expression of normal, fully functional avb3 enabled tumor growth in bone (incidence: 4/4), whereas avb3 (À), inactive or constitutively active mutants of avb3 did not (incidence: 0/4, 0/6 and 1/7, respectively) within a 35-day-period. This response appeared to be bone-specific in comparison to the subcutis where tumor incidence was greater than 60% for all groups. Interestingly, bone residing prostate cancer cells expressing normal or dis-regulated avb3 (either inactive of constitutively active), but not those lacking b3 promoted bone gain or afforded protection from bone loss in the presence or absence of histologically detectable tumor 35 days following implantation. As bone is replete with ligands for b3 integrin, we next demonstrated that avb3 integrin activation on tumor cells is essential for the recognition of key bone-specific matrix proteins. As a result, prostate cancer cells expressing fully functional but not dis-regulated avb3 integrin are able to control their own adherence and migration to bone matrix, functions that facilitate tumor growth and control bone lesion development.
Cross-talk between the major angiogenic growth factor, VEGF, and integrin cell adhesion receptors has emerged recently as a critical factor in the regulation of angiogenesis and tumor development. However, the molecular mechanisms and consequences of this intercommunication remain unclear. Here, we define a mechanism whereby integrin ␣v3, through activation, clustering, and signaling by means of p66 Shc (Src homology 2 domain containing), regulates the production of VEGF in tumor cells expressing this integrin. Tumors with ''activatable'' but not ''inactive'' 3 integrin secrete high levels of VEGF, which in turn promotes extensive neovascularization and augments tumor growth in vivo. This stimulation of VEGF expression depends upon the ability of ␣v3 integrin to cluster and promote phosphorylation of p66 Shc. These observations identify a link between 3 integrins and VEGF in tumor growth and angiogenesis and, therefore, may influence anti-integrin as well as anti-VEGF therapeutic strategies.activation ͉ angiogenesis ͉ Src homology 2 domain containing
While the survival rate for early detected cancers is high, once a cancer metastasizes to bone, it is incurable. Interestingly, patients without visible metastases display abnormal bone formation and resorption suggesting a link between primary cancers and the bone microenvironment prior to metastasis and this link likely facilitates preparation of the pre-metastatic niche. We hypothesized that communication from the primary tumor would result in bone remodeling alterations and that platelets could facilitate this communication. Using three tumor models, we demonstrate that primary tumor growth stimulates bone formation measured by microcomputed tomography (microCT). Further, platelet depletion prevented tumor-induced bone formation highlighting the importance of platelets in the communication between tumors and the bone microenvironment. Finally, we determine that platelets sequester a variety of tumor-derived proteins, TGF-β1 and MMP-1 in particular, which regulate bone formation. Thus, our data reveals that platelets function as mediators of tumor-bone communication prior to metastasis.
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