Prostate cancer specific integrin αvβ3 modulates bone metastatic growth and tissue remodeling

Abstract

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.

Cathepsin H Mediates the Processing of Talin and Regulates Migration of Prostate Cancer Cells

“…It has been reported that ␣ v ␤ 3 -integrin is associated with malignancy and invasion of primary prostate cancer cells (51). Our results demonstrate that the specific inhibition of CtsH promotes the activation of ␣ v ␤ 3 -integrin on migrating PC-3 cells.…”

TEAD1 and c-Cbl are novel prostate basal cell markers that correlate with poor clinical outcome in prostate cancer

“…The basal cell profile was consistent with a proliferative phenotype, with expression of CXCL1, NBS1 and RPA, all of which encode proteins shown earlier to promote proliferation (Chiang et al, 2003;Li et al, 2004;Givalos et al, 2007). The expression of aV integrin has earlier been described in metastatic prostate cancer (McCabe et al, 2007) but not in benign prostate cells, where it may have a role in adhesion to the basement membrane.…”

Integrins in prostate cancer progression

“…These lesions are osteoblastic or osteolytic and are frequently detected in prostate cancer patients (over 80% of prostate cancer patients have established bone metastasis at autopsy (Koeneman et al 1999)). A recent study has shown that the a v b 3 integrin promotes bone gain mediated by prostate cancer cells that metastatize to the bone and point to a v b 3 as a potential therapeutic target to block prostate cancer osteoblastic lesions (Keller & Brown 2004, McCabe et al 2007. Besides therapeutic applications, other uses of integrin inhibitors are in the area of imaging and specific delivery of a drug to cancer cells (Chen et al 2001, Moschos et al 2007, Li et al 2008.…”