Loss of cell‐contact regulation and altered responses to autocrine motility factor correlate with increased malignancy in prostate cancer cells

Abstract

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 (PC3M) 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 lowmetastatic PC-3 cells migrated primarily along the wound edge while individual high-metastatic PC3M cells entered the cellfree 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.o 199.5 Wiley-Liss, Inc.Although morphological markers of colorectal tumor malignancy, recurrence and progression have been described in some detail, biomarkers which are fully informative of the events leading to the acquisition of an invasive phenotype are required for concrete prognostic and treatment relevance (Risio et al., 1993). Abnormal cell-cell and cell-extracellular matrix interactions which mediate aspects of invasion and metastasis are the result of multiple genetic aberrations (Fearon and Vogelstein, 1990); for example, the DCC gene located on chromosome 18q encodes a protein with homology to the cell-cell adhesion molecule N-CAM, whose expression is reduced or absent in the majority of colorectal carcinomas (Fearon et al., 1990). This suggests that loss of intercellular adhesiveness and the resulting enhanced potential for migration might be paramount during the invasion of these tumors. Studies centering on the identification of factors which regulate and direct cellular movement have elucidated a group of motility factors whose primary function is thought to be regulation of cellular kinesis (Stoker and Gherardi, 1991).Tumor cell autocrine motility factor (AMF) was originally distinguished by its ability to induce the directed (chemotactic) and random (chemokinetic...

Contribution of functional voltage‐gated Na+ channel expression to cell behaviors involved in the metastatic cascade in rat prostate cancer: I. lateral motility

“…These observations appear to contrast earlier reports suggesting a positive relationship between tumor cell motility and metastatic potential (e.g., Mohler et al, 1988). However, an apparent lack of correlation between basal migration of strongly versus weakly metastatic PCa cell lines has been reported and could be related to the distinct patterns of migration undergone by cells of different metastatic abilities (e.g., Silletti et al, 1995). In particular, speed of movement may not be the only variable relevant to malignant cell motility, and other characteristics such as co-ordination (i.e., directionality) of movement may also be an important factor (e.g., Djamgoz et al, 2001).…”

“…Cells were plated in 35 mm Petri dishes at an initial density of 15 Â 10 4 cells/dish and allowed to settle for 24 h. Lateral motility was assessed by a monolayer wound assay (Silletti et al, 1995;Peck and Isacke, 1996). Analysis of the closure of the wound was performed as follows.…”

Bioenergetics of rat prostate cancer cell migration

“…Previous studies have shown that human and rodent prostate cancer tissues and cell lines produce a variety of autocrine factors [24,28], including epidermal growth factor [22,23,25,26,29], transforming growth factor alpha [22,23,27,30], fibroblast growth factor [31], interleukin 6 [17], androgen-induced growth factor [18], neurotensin [19], parathyroid hormone-related protein [20], insulin-like growth factors I and II [21], and autocrine motility factor [16,32]. In future studies, we intend to identify the various factors produced by prostate cancer cells that regulate energy metabolism.…”

“…To do so, we measured ATP content and migration of MatLu cells grown in conditioned medium with or without added glucose. While conditioned medium from MatLu cells has never been characterized, we hypothesized that MatLu cells produce several autocrine growth factors, as do other prostate cancer cell lines [16][17][18][19][20][21][22][23][24][25][26][27].…”

The crystal structure of a multifunctional protein: Phosphoglucose isomerase/autocrine motility factor/neuroleukin

“…On signal transduction, AMF binds to a cell surface glycoprotein of 78 kDa (19)(20)(21), implying that AMF is the natural ligand of the 78-kDa glycoprotein (17). AMF secreted by Gc-4 PF murine fibrosarcoma cells (10) has PGI activity, whereas rabbit heart PGI can stimulate mouse fibrosarcoma cell motility similar to that of endogenous AMF.…”