期刊
ONCOGENE
卷 26, 期 42, 页码 6238-6243出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1210429
关键词
prostate cancer; metastasis; bone; integrins
资金
- NCI NIH HHS [R01 CA126847-06, CA1172462, R01 CA126847, R01 CA126847-05A1] Funding Source: Medline
- NIAMS NIH HHS [1P30 AR-050953, P30 AR050953] Funding Source: Medline
- NIDDK NIH HHS [DK060933, R01 DK060933-04, R01 DK060933] Funding Source: Medline
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 alpha v beta 3 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 (-), inactive or constitutively active mutants of alpha v beta 3 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 alpha v beta 3 ( either inactive of constitutively active), but not those lacking beta 3 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 beta 3 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.
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