Abstract
Many similarities exist between the stroma at sites of wound repair and reactive stroma in cancer. Common features include an elevated stromal cell proliferation, altered expression of matrix components, elevated expression of TGFβ-1, neovascularization, and expression of several common stromal markers. In addition, proliferative stromal cells at these sites generally express myodifferentiation markers. A comparison between the many common features and the biologically active molecules observed in reactive stroma in carcinoma and reactive stroma in wound repair is discussed in this review. An extended analysis of the literature suggests a functional link between mechanisms in wound repair response and the stromal reaction in many cancers including prostate cancer. We propose in this review, that the fundamental mechanisms of stroma in providing a rapid response to altered homeostasis in wounding, also provides for a tumor-regulating stromal microenvironment in cancer. The functional consequences of this stromal response to carcinoma progression and how the stromal response might be used in extended diagnosis and in therapeutic approaches are discussed.
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Weiss L: In: Weiss L (ed) Cell and Tissue Biology: A Textbook of Histology. Urban & Schwarsenberg, Baltimore, 1988, pp 1-65
McNeal JE: Normal histology of the prostate. Am J Surg Pathol 12: 619-33, 1988
Shapiro E, Hartanto V, Lepor H: Quantifying the smooth muscle content of the prostate using double-immunoenzymatic staining and color assisted image analysis. J Urol 147: 1167-70, 1992
Shapiro E, Hartanto V, Lepor H: Anti-desmin vs. anti-actin for quantifying the area density of prostate smooth muscle. Prostate 20: 259-67, 1992
Castellucci E, Prayer-Galetti T, Roelofs M, Pampinella F, Faggian L, Gardiman M, Pagano F, Sartore S: Cytoskeletal and cytocontractile protein composition of stromal tissue in normal, hyperplastic, and neoplastic human prostate. An immunocytochemical study with monoclonal antibodies. Ann NY Acad Sci 784: 496-508, 1996
Prins GS, Birch L: The developmental pattern of androgen receptor expression in rat prostate lobes is altered after neonatal exposure to estrogen. Endocrinology 136: 1303-1314, 1995
Cunha GR, Fujii H, Neubauer BL, Shannon JM, Sawyer L, Reese BA: Epithelial-mesenchymal interactions in prosate development. I. Morphological observations of prostatic induction by urogenital sinus mesenchyme in epithelium of the adult rodent urinary bladder. J Cell Biol 96: 1662-1670, 1983
Neubauer BL, Chung LWK, McCormick KA, Taguchi O, Thompson TC, Cunha GR: Epithelial-mesenchymal interactions in prostatic development. II. Biochemical observations of prostatic induction by urogenital sinus mesenchyme in epithelium of the adult rodent urinary bladder. J Cell Biol 96: 1671-1676, 1983
Ronnov-Jessen L, Petersen OW, Bissell MJ: Cellular changes involved in conversion of normal to malignant breast: Importance of the stromal reaction. Physiol Rev 76: 69-125, 1996
Hewitt RE, Powe DG, Carter GI, Turner DR: Desmoplasia and its relevance to colorectal tumour invasion. Int J Cancer 53: 62-9, 1993
Lazard D, Sastre X, Frid MG, Glukhova MA, Thiery JP, Koteliansky VE: Expression of smooth muscle-specific proteins in myoepithelium and stromal myofibroblasts of normal and malignant human breast tissue. Proc Natl Acad Sci USA 90: 999-1003, 1993
Ronnov-Jessen L, Petersen OW, Koteliansky VE, Bissell MJ: The origin of the myofibroblasts in breast cancer. Recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. J Clin Invest 95: 859-73, 1995
Lochter A, Galosy S, Muschler J, Freedman N, Werb Z, Bissell MJ: Matrix metalloproteinase stromelysin-1 triggers a cascade of molecular alterations that leads to stable epithelial-to-mesenchymal conversion and a premalignant phenotype in mammary epithelial cells. J Cell Biol 139: 1861-72, 1997
Thomasset N, Lochter A, Sympson CJ, Lund LR, Williams DR, Behrendtsen O, Werb Z, Bissell MJ: Expression of autoactivated stromelysin-1 in mammary glands of transgenic mice leads to a reactive stroma during early development. Am J Pathol 153: 457-67, 1998
Lieubeau B, Garrigue L, Barbieux I, Meflah K, Gregoire M: The role of transforming growth factor beta 1 in the fibroblastic reaction associated with rat colorectal tumor development. Cancer Res 54: 6526-32, 1994
Owens GK: Regulation of differentiation of vascular smooth muscle cells. Physiol Rev 75: 487-517, 1995
Frid MG, Shekhonin BV, Koteliansky VE, Glukhova MA: Phenotypic changes of human smooth muscle cells during development: Late expression of heavy caldesmon and calponin. Dev Biol 153: 185-193, 1992
Dvorak HF: Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315: 1650-9, 1986
Gregoire M, Lieubeau B: The role of fibroblasts in tumor behavior. Cancer Metast Rev 14: 339-50, 1995
Sieweke MH, Bissell MJ: The tumor-promoting effect of wounding: a possible role for TGF-beta-induced stromal alterations. Crit Rev Oncog 5: 297-311, 1994
Anderson GR, Stoler DL, Scarcello LA: Normal fibroblasts responding to anoxia exhibit features of the malignant phenotype. J Biol Chem 264: 14885-92, 1989
Martins-Green M, Bissell MJ: Localization of 9E3/CEF-4 in avian tissues: expression is absent in Rous sarcoma virus-induced tumors but is stimulated by injury. J Cell Biol 110: 581-95, 1990
Martins-Green M, Boudreau N, Bissell MJ: Inflammation is responsible for the development of wound-induced tumors in chickens infected with Rous sarcoma virus. Cancer Res 54: 4334-41, 1994
Hofer SO, Shrayer D, Reichner JS, Hoekstra HJ, Wanebo HJ: Wound-induced tumor progression: a probable role in recurrence after tumor resection. Arch Surg 133: 383-9, 1998
Dvorak HF, Harvey VS, Estrella P, Brown LF, McDonagh J, Dvorak AM: Fibrin containing gels induce angiogenesis. Implications for tumor stroma generation and wound healing. Lab Invest 57: 673-86, 1987
Garin-Chesa P, Old LJ, Rettig WJ: Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc Natl Acad Sci USA 87: 7235-9, 1990
Schmid P, Itin P, Cherry G, Bi C, Cox DA: Enhanced expression of transforming growth factor-beta type I and type II receptors in wound granulation tissue and hypertrophic scar. Am J Pathol 152: 485-93, 1998
Greenberg NN, DeMayyo F, Finegold M, Medina D, Tilley W, Aspinall JO, Cunha GR, Donjacour AA, Matusik RJ, Rosen JM: Prostate cancer in a transgenic mouse. Proc Natl Acad Sci USA 92: 3439-3443, 1995
Kasper S, Sheppard PC, Yan Y, Pettigrew N, Borowsky AD, Prins GS, Dodd JG, Duckworth ML, Matusik RJ: Development, progression, and androgen-dependence of prostate tumors in probasin-large T antigen transgenic mice: a model for prostate cancer [corrected and republished article originally printed in Lab Invest 1998 Mar; 78(3): 319-33]. Lab Invest 78: i-xv, 1998
Cunha GR, Chung LWK: Stromal-epithelial interactions-I. Induction of prostatic phenotype in urothelium of testicular feminized (Tfm/y) mice. J Ster Biochem 14: 1317-1321, 1981
Cunha GR, Bigsby RM, Cooke PS, Sugimura Y: Stromal-epithelial interactions in adult organs. Cell Differ 17: 137-148, 1985
Cunha GR, Hayward SW, Dahiya R, Foster BA: Smooth muscle-epithelial interactions in normal and neoplastic prostatic development. Acta Anatomica 155: 63-72, 1996
Thompson TC, Southgate J, Kitchener G, Land H: Multistage carcinogenesis induced by ras and myc oncogenes in a reconstituted organ. Cell 56: 917-30, 1989
Merz VW, Miller GJ, Krebs T, Timme TL, Kadmon D, Park SH, Egawa S, Scardino PT, Thompson TC: Elevated transforming growth factor-beta 1 and beta 3 mRNA levels are associated with ras+myc-induced carcinomas in reconstituted mouse prostate: evidence for a paracrine role during progression. Mol Endocrinol 5: 503-13, 1991
Thompson TC, Timme TL, Kadmon D, Park SH, Egawa S, Yoshida K: Genetic predisposition and mesenchymal-epithelial interactions in ras+myc-induced carcinogenesis in reconstituted mouse prostate. Mol Carcinog 7: 165-79, 1993
Hayashi N, Cunha GR, Wong YC: Influence of male genital tract mesenchymes on differentiation of Dunning prostatic adenocarcinoma. Cancer Res 50: 4747-4754, 1990
Hayashi N, Cunha GR: Mesenchyme-induced changes in neoplastic characteristics of the Dunning prostatic adenocarcinoma. Cancer Res 51: 4924-4930, 1991
Chung LWK, Chang S-M, Bell C, Zhau HE, Ro JY, von Eschenbach AC: Co-inoculation of tumorigenic rat prostate mesenchymal cells with non-tumorigenic epithelial cells results in the development of carcinosarcoma in syngeneic and athymic animals. Internat J Canc 43: 1179-1187, 1989
Chung LWK: Fibroblasts are critical determinants in prostatic cancer growth and dissemination. Canc Metas Rev 10: 263-274, 1991
Wu HC, Hsieh JT, Gleave ME, Brown NM, Pathak S, Chung LW: Derivation of androgen-independent human LNCaP prostatic cancer cell sublines: role of bone stromal cells. Int J Cancer 57: 406-12, 1994
Robbins SE, Shu WP, Kirschenbaum A, Levine AC, Miniati DN, Liu BC: Bone extracellular matrix induces homeobox proteins independent of androgens: possible mechanism for androgen-independent growth in human prostate cancer cells. Prostate 29: 362-70, 1996
Chung LW: The role of stromal-epithelial interaction in normal and malignant growth. Cancer Surv 23: 33-42, 1995
Thompson TC, Truong LD, Timme TL, Kadmon D, McCune BK, Flanders KC, Scardino PT, Park SH: Transforming growth factor B1 as a biomarker for prostate cancer. J Cel Biochem 16H: 54-61, 1992
Truong LD, Kadmon D, McCune BK, Flanders KC, Scardino PT, Thompson TC: Association of transforming growth factor-B1 with prostate cancer: An immunohistochemical study. Human Pathology 24: 4-9, 1993
Steiner MS, Zhou ZZ, Tonb DC, Barrack ER: Expression of transforming growth factor-beta 1 in prostate cancer. Endocrinology 135: 2240-7, 1994
Gerdes MJ, Larsen M, McBride L, Dang TD, Lu B, Rowley DR: Localization of transforming growth factorbeta1 and type II receptor in developing normal human prostate and carcinoma tissues. J Histochem Cytochem 46: 379-88, 1998
Kim IY, Ahn HJ, Zelner DJ, Shaw JW, Lang S, Kato M, Oefelein MG, Miyazono K, Nemeth JA, Kozlowski JM, Lee C: Loss of expression of transforming growth factor beta type I and type II receptors correlates with tumor grade in human prostate cancer tissues. Clin Cancer Res 2: 1255-1261, 1996
Williams RH, Stapleton AMF, Yang G, Truong LD, Rogers E, Timme TL, Wheeler TM, Scardino PT, Thompson TC: Reduced levels of transforming growth factor beta receptor type II in human prostate cancer: An immunohistochemical study. Clin Cancer Res 2: 635-640, 1996
Guo Y, Jacobs SC, Kyprianou N: Down-regulation of protein and mRNA expression for transforming growth factor-beta (TGF-beta1) type I and type II receptors in human prostate cancer. Int J Cancer 71: 573-9, 1997
Gerdes MJ, Dang TD, Lu B, Larsen M, McBride L, Rowley DR: Androgen-regulated proliferation and gene transcription in a prostate smooth muscle cell line (PS-1). Endocrinology 137: 864-872, 1996
Gerdes MJ, Dang TD, Larsen M, Rowley DR: Transforming growth factor-betal induces nuclear to cytoplasmic distribution of androgen receptor and inhibits androgen response in prostate smooth muscle cells. Endocrinology 139: 3569-77, 1998
Steiner MS, Barrack ER: Transforming growth factor-beta1 overproduction in prostate cancer: effects on growth in vivoand in vitro. Mol Endocrinol 6: 15-25, 1992
Lyne JC, Melhem MF, Finley GG, Wen D, Liu N, Deng DH, Salup R: Tissue expression of neu differentiation factor/heregulin and its receptor complex in prostate cancer and its biologic effects on prostate cancer cells in vitro. Cancer J Sci Am 3: 21-30, 1997
Peehl DM, Cohen P, Rosenfeld RG: The insulin-like growth factor system in the prostate. World J Urol 13: 306-11, 1995
Tennant MK, Thrasher JB, Twomey PA, Drivdahl RH, Birnbaum RS, Plymate SR: Protein and messenger ribonucleic acid (mRNA) for the type 1 insulin-like growth factor (IGF) receptor is decreased and IGF-Il mRNA is increased in human prostate carcinoma compared to benign prostate epithelium. J Clin Endocrinol Metab 81: 3774-82, 1996
Tennant MK, Thrasher JB, Twomey PA, Birnbaum RS, Plymate SR: Insulin-like growth factor-binding proteins (IGFBP)-4,-5, and-6 in the benign and malignant human prostate: IGFBP-5 messenger ribonucleic acid localization differs from IGFBP-5 protein localization. J Clin Endocrinol Metab 81: 3783-92, 1996
Reubi JC, Waser B, Schaer JC, Markwalder R: Somatostatin receptors in human prostate and prostate cancer. J Clin Endocrinol Metab 80: 2806-14, 1995
Mazzucchelli L, Loetscher P, Kappeler A, Uguccioni M, Baggiolini M, Laissue JA, Mueller C: Monocyte chemoattractant protein-1 gene expression in prostatic hyperplasia and prostate adenocarcinoma. AmJ Pathol 149: 501-9, 1996
Dalal R, Djakiew D: Molecular characterization of neurotrophin expression and the corresponding tropomyosin receptor kinases (trks) in epithelial and stromal cells of the human prostate. Mol Cell Endocrinol 134: 15-22, 1997
Hiramatsu M, Maehara I, Ozaki M, Harada N, Orikasa S, Sasano H: Aromatase in hyperplasia and carcinoma of the human prostate. Prostate 31: 118-24, 1997
Humphrey PA, Zhu X, Zarnegar R, Swanson PE, Ratliff TL, Vollmer RT, Day ML: Hepatocyte growth factor and its receptor (c-MET) in prostatic carcinoma. Am J Pathol 147: 386-96, 1995
Bogenrieder T, Finstad CL, Freeman RH, Papandreou CN, Scher HI, Albino AP, Reuter VE, Nanus DM: Expression and localization of aminopeptidase A, aminopeptidase N, and dipeptidyl peptidase IV in benign and malignant human prostate tissue. Prostate 33: 225-32, 1997
Story MT: Regulation of prostate growth by fibroblast growth factors. World J Urol 13: 297-305, 1995
Yan G, Fukabori Y, Nikolaropoulos S, Wang F, McKeehan WL: Heparin-binding keratinocyte growth factor (FGF-7) is a candidate stromal-to-epithelial cell prostate andromedin. Molecular Endocrinology 6: 2123-2128, 1992
Rowley DR, Tindall DJ: Responses of NBT-II bladder carcinoma cells to conditioned medium from normal fetal urogenital sinus. Cancer Res 47: 2955-2960, 1987
Rowley DR: Characterization of a fetal urogenital sinus mesenchymal cell line U4F: Secretion of a negative growth regulatory activity. In VitroCell Dev Biol 28: 29-38, 1992
Rowley DR, Dang TD, Larsen M, Gerdes MJ, McBride L, Lu B: Purification of a novel protein (ps20) from urogenital sinus mesenchymal cells with growth inhibitory properties in vitro. J Biol Chem 270: 22058-22065, 1995
Larsen M, Ressler SJ, Lu B, Gerdes MJ, McBride L, Dang TD, Rowley DR: Molecular cloning and expression of ps20 growth inhibitor. A novelWAP-type ‘four-disulfide core’ domain protein expressed in smooth muscle. J Biol Chem 273: 4574-84, 1998
Leung HY, Mehta P, Gray LB, Collins AT, Robson CN, Neal DE; Keratinocyte growth factor expression in hormone insensitive prostate cancer. Oncogene 15: 1115-20, 1997
Levine AC, Liu XH, Greenberg PD, Eliashvili M, Schiff JD, Aaronson SA, Holland JF, Kirschenbaum A: Androgens induce the expression of vascular endothelial growth factor in human fetal prostatic fibroblasts. Endocrinology 139: 4672-8, 1998
Jackson MW, Bentel JM, Tilley WD: Vascular endothelial growth factor (VEGF) expression in prostate cancer and benign prostatic hyperplasia. J Urol 157: 2323-8, 1997
Bigler SA, Deering RE, Brawer MK: Comparison of microscopic vascularity in benign and malignant prostate tissue. Hum Pathol 24: 220-6, 1993
Fukumura D, Xavier R, Sugiura T, Chen Y, Park EC, Lu N, Selig M, Nielsen G, Taksir T, Jain RK, Seed B: Tumor induction of VEGF promoter activity in stromal cells. Cell 94: 715-25, 1998
Vollmer G: Expression of tenascin during carcinogenesis and involution of hormone-dependent tissues. Biochem Cell Biol 72: 505-14, 1994
Vollmer G, Michna H, Schneider MR: Tumorigenesis disrupts hormonal regulation of tenascin expression in regressing Dunning R 3327 H prostate carcinoma. Cancer Lett 101: 185-92, 1996
Ibrahim SN, Lightner VA, Ventimiglia JB, Ibrahim GK, Walther PJ, Bigner DD, Humphrey PA: Tenascin expression in prostatic hyperplasia, intraepithelial neoplasia, and carcinoma. Hum Pathol 24: 982-9, 1993
Xue Y, Li J, Latijnhouwers MA, Smedts F, Umbas R, Aalders TW, Debruyne FM, De La Rosette JJ, Schalken JA: Expression of periglandular tenascin-C and basement membrane laminin in normal prostate, benign prostatic hyperplasia and prostate carcinoma. Br J Urol 81: 844-51, 1998
Ricciardelli C, Mayne K, Sykes PJ, Raymond WA, McCaul K, Marshall VR, Horsfall DJ: Elevated levels of versican but not decorin predict disease progression in earlystage prostate cancer. Clin Cancer Res 4: 963-71, 1998
Wood M, Fudge K, Mohler JL, Frost AR, Garcia F, Wang M, Stearns ME: In situhybridization studies of metalloproteinases 2 and 9 and TIMP-1 and TIMP-2 expression in human prostate cancer. Clin Exp Metas 15: 246-58, 1997
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Rowley, D.R. What Might A Stromal Response Mean to Prostate Cancer Progression?. Cancer Metastasis Rev 17, 411–419 (1998). https://doi.org/10.1023/A:1006129420005
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DOI: https://doi.org/10.1023/A:1006129420005