Prostate and bone fibroblasts induce human prostate cancer growth in vivo

implications for bidirectional tumor-stromal cell interaction in prostate carcinoma growth and metastasis.

M. E. Gleave, J. T. Hsieh, A. C. von Eschenbach, L. W. Chung

Research output: Contribution to journalArticle

163 Citations (Scopus)

Abstract

Prostate cancer selectively metastasizes to the axial skeleton to produce osteoblastic lesions, which suggests that bidirectional paracrine interactions exist between prostate cancer and bone cells. To evaluate the role of tumor-stromal cell interaction and stromal-specific growth factors in prostate cancer growth and dissemination, we coinoculated nontumorigenic human prostate cancer cells (LNCaP) and various tissue-specific fibroblasts subcutaneously in athymic mice. LNCaP tumors were induced most consistently by human bone fibroblasts (62%), followed by two prostate fibroblast cell lines (31% and 17%), but not by lung, kidney, or embryonic 3T3 fibroblasts. Carcinomas formed preferentially in male hosts, demonstrating in vivo androgen sensitivity. Immunohistochemical and biochemical techniques confirmed the human prostate component of these tumors and were paralleled by elevations in serum prostate specific antigen. In vitro mitogenic assays revealed a two-to three-fold bidirectional stimulation between LNCaP and bone or prostate fibroblast conditioned media, but not lung, kidney, or 3T3 fibroblast conditioned media. A novel method developed to deliver concentrated bone or prostate fibroblast conditioned media in vivo using a slowly absorbed matrix (gelfoam) also induced tumor formation, emphasizing the importance of fibroblast growth factors in LNCaP tumor formation. Northern analysis identified the stromal compartment as the primary source of extracellular matrix (collagen, fibronectin), while only LNCaP cells expressed transforming growth factor alpha. Although LNCaP and stromal cells express basic fibroblast growth factor (bFGF), the bidirectional paracrine-mediated mitogenic activity between these cells is not inhibited by anti-bFGF antibodies, suggesting that other undefined growth factors may be involved in stimulating LNCaP growth. These observations illustrate the importance of stromal-epithelial interaction in prostate tumor growth and suggest that extracellular matrix and paracrine-mediated growth factors play a role in prostate cancer growth and metastasis.

Original languageEnglish (US)
Pages (from-to)1151-1159
Number of pages9
JournalJournal of Urology
Volume147
Issue number4
StatePublished - Apr 1992

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Stromal Cells
Cell Communication
Prostate
Prostatic Neoplasms
Fibroblasts
Neoplasm Metastasis
Carcinoma
Bone and Bones
Growth
Conditioned Culture Medium
Neoplasms
Intercellular Signaling Peptides and Proteins
Fibroblast Growth Factor 2
Extracellular Matrix
Absorbable Gelatin Sponge
Kidney
Bone Neoplasms
Lung
Transforming Growth Factor alpha
Fibroblast Growth Factors

ASJC Scopus subject areas

  • Urology

Cite this

Prostate and bone fibroblasts induce human prostate cancer growth in vivo : implications for bidirectional tumor-stromal cell interaction in prostate carcinoma growth and metastasis. / Gleave, M. E.; Hsieh, J. T.; von Eschenbach, A. C.; Chung, L. W.

In: Journal of Urology, Vol. 147, No. 4, 04.1992, p. 1151-1159.

Research output: Contribution to journalArticle

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abstract = "Prostate cancer selectively metastasizes to the axial skeleton to produce osteoblastic lesions, which suggests that bidirectional paracrine interactions exist between prostate cancer and bone cells. To evaluate the role of tumor-stromal cell interaction and stromal-specific growth factors in prostate cancer growth and dissemination, we coinoculated nontumorigenic human prostate cancer cells (LNCaP) and various tissue-specific fibroblasts subcutaneously in athymic mice. LNCaP tumors were induced most consistently by human bone fibroblasts (62{\%}), followed by two prostate fibroblast cell lines (31{\%} and 17{\%}), but not by lung, kidney, or embryonic 3T3 fibroblasts. Carcinomas formed preferentially in male hosts, demonstrating in vivo androgen sensitivity. Immunohistochemical and biochemical techniques confirmed the human prostate component of these tumors and were paralleled by elevations in serum prostate specific antigen. In vitro mitogenic assays revealed a two-to three-fold bidirectional stimulation between LNCaP and bone or prostate fibroblast conditioned media, but not lung, kidney, or 3T3 fibroblast conditioned media. A novel method developed to deliver concentrated bone or prostate fibroblast conditioned media in vivo using a slowly absorbed matrix (gelfoam) also induced tumor formation, emphasizing the importance of fibroblast growth factors in LNCaP tumor formation. Northern analysis identified the stromal compartment as the primary source of extracellular matrix (collagen, fibronectin), while only LNCaP cells expressed transforming growth factor alpha. Although LNCaP and stromal cells express basic fibroblast growth factor (bFGF), the bidirectional paracrine-mediated mitogenic activity between these cells is not inhibited by anti-bFGF antibodies, suggesting that other undefined growth factors may be involved in stimulating LNCaP growth. These observations illustrate the importance of stromal-epithelial interaction in prostate tumor growth and suggest that extracellular matrix and paracrine-mediated growth factors play a role in prostate cancer growth and metastasis.",
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