Inhibition of vimentin or beta1 integrin reverts morphology of prostate tumor cells grown in laminin-rich extracellular matrix gels and reduces tumor growth in vivo.
Prostate epithelial cells grown embedded in laminin-rich extracellular matrix (lrECM) undergo morphologic changes that closely resemble their architecture in vivo. In this study, growth characteristics of three human prostate epithelial sublines derived from the same cellular lineage, but displaying different tumorigenic and metastatic properties in vivo, were assessed in three-dimensional lrECM gels. M12, a highly tumorigenic and metastatic subline, was derived from the immortalized, prostate epithelial P69 cell line by selection in athymic, nude mice and found to contain a deletion of 19p-q13.1. The stable reintroduction of an intact human chromosome 19 into M12 resulted in a poorly tumorigenic subline, designated F6. When embedded in lrECM gels, the parental, nontumorigenic P69 line produced acini with clearly defined lumena. Immunostaining with antibodies to beta-catenin, E-cadherin, or alpha6 and beta1 integrins showed polarization typical of glandular epithelium. In contrast, the metastatic M12 subline produced highly disorganized cells with no evidence of polarization. The F6 subline reverted to acini-like structures exhibiting basal polarity marked with integrins. Reducing either vimentin levels via small interfering RNA interference or the expression of alpha6 and beta1integrins by the addition of blocking antibodies, reorganized the M12 subline into forming polarized acini. The loss of vimentin significantly reduced M12-Vim tumor growth when assessed by s.c. injection in athymic mice. Thus, tumorigenicity in vivo correlated with disorganized growth in three-dimensional lrECM gels. These studies suggest that the levels of vimentin and beta1 integrin play a key role in the homeostasis of the normal acinus in prostate and that their dysregulation may lead to tumorigenesis.
Zhang
Xueping
X
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University-Medical Campus, P.O. Box 980614, Richmond, VA 23298-0614, USA.
Fournier
Marcia V
MV
Ware
Joy L
JL
Bissell
Mina J
MJ
Yacoub
Adly
A
Zehner
Zendra E
ZE
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects*; D048430:Cell Shape / Q000187:drug effects; D005109:Extracellular Matrix / Q000737:chemistry / Q000502:physiology; D005782:Gels / Q000494:pharmacology*; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D007797:Laminin / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D011471:Prostatic Neoplasms / Q000473:pathology*; D034741:RNA, Small Interfering / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014746:Vimentin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D005782:Gels; D019012:Integrin beta1; D007797:Laminin; D034741:RNA, Small Interfering; D014746:Vimentin