Loss of cell-contact regulation and altered responses to autocrine motility factor correlate with increased malignancy in prostate cancer cells.
Tumor cell migration and proliferation in new organ environments are critical steps in cancer progression and can be modulated by tumor- and host-secreted molecules. Autocrine motility factor (AMF) is a tumor-secreted cytokine which regulates growth and motility by a receptor-mediated pathway. The AMF receptor, a 78-kDa cell surface glycoprotein (gp78), is regulated by cell contact in normal fibroblastic and bladder cells; however, this mechanism is disrupted during tumor progression. A prostatic carcinoma cell line which is low- to non-metastatic in nude mice (PC-3) and a derived metastatic variant (PC-3M) were examined to determine if gp78 cell density regulation is involved in prostate cancer progression. Both cell lines expressed gp78 and, although the basal migration of the parental PC-3 cells was higher than that of the metastatic variant, only the PC-3M cells were capable of responding to tumor-derived AMF with increased motility. Furthermore, these cells exhibited differential patterns of wound closure in an experimental system whereby the low-metastatic PC-3 cells migrated primarily along the wound edge while individual high-metastatic PC-3M cells entered the cell-free wound area directly. Cell surface gp78 distribution distinguished the cell populations with a markedly concentrated display of gp78 in polarized capped regions on the surface of the metastatic cells. Cell-cell contact down-regulated gp78 expression in the parental, but not the metastatic, cells, and mitogenic responses to exogenous AMF differed between these cell lines as well. In this model, metastasis appears to be associated with aberrant regulation of gp78 expression and distribution, coupled with enhanced exploitation of AMF's locomotory and proliferative effects.
Silletti
S
S
Metastasis Research Program, Michigan Cancer Foundation, Detroit 48201, USA.
Yao
J P
JP
Pienta
K J
KJ
Raz
A
A
D002465:Cell Movement / Q000187:drug effects; D003260:Contact Inhibition; D005956:Glucose-6-Phosphate Isomerase / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008938:Mitosis / Q000187:drug effects; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000473:pathology*; D060285:Receptors, Autocrine Motility Factor; D018121:Receptors, Cytokine / Q000378:metabolism; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases
D018121:Receptors, Cytokine; C555000:AMFR protein, human; C555002:Amfr protein, mouse; D060285:Receptors, Autocrine Motility Factor; D044767:Ubiquitin-Protein Ligases; D005956:Glucose-6-Phosphate Isomerase