Fibroblast-mediated acceleration of human epithelial tumor growth in vivo.

Abstract

Transformed fibroblasts coinoculated with epithelial cells accelerated the growth and shortened the latency period of human epithelial tumors in athymic mice. Addition of NbF-1 fibroblasts caused epithelial tumors to grow from five marginally tumorigenic or "nontumorigenic" (nontumorforming) human tumor cell lines or strains: PC-i (prostate), WH (bladder), , and cells derived from the ascites fluids of patients with metastatic renal pelvic or prostate cancers. Evidence for the human and epithelial nature of these experimental tumors was provided by histologic, immunohistochemical, Southern and dot-blot hybridization, and cytogenetic analyses. Transformed fibroblasts induced predominantly carcinosarcomas, whereas nontumorigenic fibroblasts (NIH 3T3) and lethally irradiated transformed fibroblasts induced exclusively carcinomas. The fibroblast-epithelial interaction appears to occur bidirectionally and does not result from cell fusion. Because coculture experiments in vitro did not demonstrate an increased cell proliferation, it appears that undefined host factors can influence tumor growth. This tumor model may be useful in drug-screening programs and in mechanistic studies of factors regulating human tumor growth and progression.Interactions between epithelium and mesenchyme mediate crucial aspects of normal development and are also believed to be important in neoplasia (1)(2)(3)(4). By employing tissuerecombination techniques, it has been demonstrated that the growth and differentiation of normal epithelium is regulated either inductively or permissively by neighboring mesenchymal components (5, 6). Studies of stromal-epithelial interaction in the prostate gland revealed that mesenchyme isolated from the fetal urogenital sinus (7, 8) but not from the prostate of newborns (9) or adults (10) can stimulate proliferation of well-differentiated adult epithelium. Mesenchymal mediation of sex steroid action on glandular epithelium has also been demonstrated. The growth of the prostate (7, 8), the regression of the mammary gland by androgen stimulation (11,12), and the growth (13) and the expression of progesterone receptors (14) by the mammary epithelium in response to estrogen have been shown to be mediated by the indirect action of sex steroids on the fibromuscular stroma.Stromal influences on epithelial neoplasia have also been documented in the salivary gland (15), the mammary gland (16), the urinary bladder (17), and the skin (18 Tumorigenicity Determinations. The athymic nude BALB/c mouse strain (20-25 g, Charles River Breeding Laboratories) was used in all experiments. Tumor volumes were calculated by the formula weight x length x height x 0.5236 (24). With the exception of the PC-3 cell line (25), our definition of "tumorigenicity" conformed to the published data. Dot Blot and Southern Hybridization. DNA was prepared from tissues and tumors according to the method described by Davis et al. (26), with slight modification to include treatment steps with proteinase K (0.2 mg/ml, Sigma) and RNase A (20 ,g/...

NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells

“…Stromal cells in cancer tissues influence the growth, invasion and metastasis of cancer cells. Growth, migration, and invasion of cancer cells were markedly accelerated by a broad spectrum of fibroblasts in vivo (Camps et al, 1990) and in vitro (Grey et al, 1989). Over 90% of pancreatic cancers originate from pancreatic duct epithelial cells, accompanied by abundant stromal components.…”

The community effect in FGF-1 mediated tumor progression of a rat bladder carcinoma does not involve a direct paracrine signaling

“…We conclude that MDCK cells exert an helper e ect promoting the growth of a limited number of FGF-1 producing cells below a threshold permitting tumor take. This helper e ect is likely to be similar to the inducing e ect of ®broblasts on tumor take (Camps et al, 1990).…”

“…The ®broblasts a ect the initial development of the tumor but the subsequent growth of the xenografts was not enhanced by ®broblasts (Hennigan et al, 1994.) The ®broblast-epithelium interactions are likely in¯uenced by host factors; however in vitro, it has been reported that coculture experiments between human epithelial tumor cells (prostatic, bladder or breast cancers) with murine ®broblasts did not result in an increase proliferation of the cancer cells (Camps et al, 1990).…”

“…Several reports demontrate the stimulatory role of ®broblasts in the development of the tumor in nude mice (Camps et al, 1990;Gregoire and Lieubeau, 1995;Hennigan et al, 1994;Loizidou et al, 1996;Nakajima, 1993;Schor, 1995). In the experiments reported here epithelial cells are also shown to exert an helper e ect for tumor growth.…”

“…Fibroblasts of di erent origins mixed with cancer cells do not grow within the tumor (Camps et al, 1990); their inducing capacities are rather linked to their production of growth/survival factors including extracellular matrix allowing a more suitable microenvironment (Paweletz and Boxberger, 1994); indeed ®broblasts can be substituted by reconstituted basement membrane and coinjection of NIH3T3 cells with Matrigel induces tumorigenicity (Fridman et al, 1992).…”