- Email: [email protected]
THE ROLES OF MYOFIBROBLASTS IN PROSTATE CARCINOGENESIS
0022-5347/04/1726-2125/0 THE JOURNAL OF UROLOGY® Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 172, 2125–2126, December 2004 Printed in U.S.A.
DOI: 10.1097/01.ju.0000145136.48668.41
Editorials THE ROLES OF MYOFIBROBLASTS IN PROSTATE CARCINOGENESIS Cancer growth and differentiation are intimately affected by the cellular and host microenvironment. Much past investigation emphasized the diagnosis and treatment of cancer based on an understanding of the diseased epithelium alone. But cancer grows as a 3-dimensional organ surrounded by host stromal cells, and with time will manifest with different malignant potentials dependent on the genetic and epigenetic backgrounds of the host. There is an urgent need to understand how the cancer microenvironment differs from the benign or normal microenvironment and what factors determine the transition from a benign to a cancerous microenvironment. Ultimately the cancerous microenvironment should be considered an attractive therapeutic target because it can augment the growth, survival, invasion and metastasis of prostate cancer cells to the skeleton or soft tissues with or without continued evolution by the cancer cells. In this issue of The Journal Singh et al (page 2421) reveal evidence linking the reactive stroma with the tissue wound healing response and discuss possible roles in prostate carcinogenesis. In this and previous studies they have proposed that the reactive stroma has a dominant role in cancer growth and differentiation, possibly through the expression and specific signaling mediated by growth factors and extracellular matrices elaborated by cancer cells and/or the surrounding stroma.1–3 In this article the authors provide an attractive working hypothesis suggesting that the reactive stroma coevolves with prostate cancer under the control of transforming growth factor-1 (TGF-1). As the result of tumor-stroma interaction, TGF-1 could be the key candidate growth factor regulating the morphological conversion of normal stromal fibroblasts to a reactive stroma, or myofibroblasts. The important functional consequences include increased growth of cancer epithelium through decreased apoptosis as demonstrated in the results. The strengths of this experimental approach are the use of primary human prostate stromal and established human prostate cancer cell lines for the study, the successful demonstration of TGF-1 promotion of prostate stromal cells to undergo myofibroblastic transition in vitro, and the validation and documentation of the functional relationship between increased myofibroblast population and decreased prostate cancer epithelial apoptosis in prostate tumors grown in mice. The latter experimental observation emphasizes the importance of the possible direct interaction between myofibroblasts and prostate cancer cells, and downplays the mechanistic contribution of confounding factors such as host immune suppression or angiogenesis. This proposed concept is in accord with previous reports on the reciprocity of cellular communication between stroma and epithelium,4, 5 the contribution of inflammation to prostate cancer development,6 bidirectional cellular interaction between prostate cancer and prostate or bone stroma,7 and the surge in growth factors, inflammatory cytokines and extracellular matrice mediated signaling that accompanies cancer growth, development and progression.8 –11 It is also conceivable that interaction between cancer epithelium and the growth factor/extracellular matrix milieu surrounding the myofibroblasts could promote an epithelium to mesenchyme transition with enhanced cancer cell invasion, migration and metastasis.12, 13 The results of this study could have
important clinical implications and practical use in the future. By defining the stromal signature we may be able to predict the malignant status of future cancer cells. By evaluating gene expression rather than morphological changes associated with the transition of fibroblasts to myofibroblasts or epithelium to mesenchyme alone we may increase the sensitivity and specificity of prostate cancer diagnosis earlier and more accurately before morphological alterations could be recognized by pathologists. Gene profiling approaches could significantly complement the conventional histomorphological evaluation of pathological specimens under the microscope since stromal response, or dysmoplastic reaction, is infrequently observed in prostate cancer specimens. Understanding the cancer microenvironment interaction could also potentially affect cancer treatment. By exploring stroma targeting14 and by co-targeting stroma and epithelium,15 the survival of mice with prostate cancer xenografts grown in bone has been improved16 and the survival of patients with the lethal phenotype of hormonal refractory and bone metastatic disease has been improved.17 Tumor microenvironment interaction deserves further investigation. Remarkably, recent experimental evidence suggests that permanent genetic and gene expression changes occur in the stroma surrounding tumor epithelium in experimental models15, 18, 19 and in clinical specimens.20 Likewise the growth, invasion and colonization of cancer cells at different organ sites and the genetics of cancer cells are also affected by host organ microenvironment.21–23 This supports the coevolutionary concept proposed by Singh et al and confirms a long held fear that cancer and stroma are moving targets that can only be effectively attacked by a combination therapy covering a broad spectrum of overlapping and clonally specific targets. To move this field forward we need to expand our current knowledge of stromal molecular biology from cell cultures to live animals, with specific emphasis on biologically and clinically relevant cancer-stroma interaction targets and models. Such investigations will lead to improved applications benefiting patients in the clinic.
2125
Leland W. K. Chung Department of Urology Molecular Urology and Therapeutics Program and Winship Cancer Institute Emory University School of Medicine Atlanta, Georgia 1. Tuxhorn, J. A., McAlhany, S. J., Yang, F., Tang, T. D. and Rowley, D. R.: Inhibition of transforming growth factor-beta activity decreases angiogenesis in a human prostate cancerreactive stroma xenograft model. Cancer Res, 62: 6021, 2002 2. Rowley, D. R.: What might a stromal response mean to prostate cancer progression? Cancer Metastasis Rev, 17: 411, 1998 3. Gerdes, M. J., Larsen, M., Dang, T. D., Ressler, S. J., Tuxhorn, J. A. and Rowley, D. R.: Regulation of rat prostate stromal cell myodifferentiation by androgen and TGF-beta1. Prostate, 58: 299, 2004 4. Lelievre, S. A., Weaver, V. M., Nickerson, J. A., Larabell, C. A., Bhaumik, A., Petersen, O. W. et al: Tissue phenotype depends on reciprocal interaction between the extracellular matrix and the structural organization of the nucleus. Proc Natl Acad Sci USA, 95: 14711, 1998 5. Chung, L. W., Gleave, M. E., Hsieh, J. T., Hong, S. J. and Zhan, H. E.: Reciprocal mesenchymal-epithelial interaction affecting
2126
6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
16.
MYOFIBROBLASTS IN PROSTATE CARCINOGENESIS
prostate tumour growth and hormonal responsiveness. Cancer Surv, 11: 91, 1991 Platz, E. A. and De Marzo, A. M.: Epidemiology of inflammation and prostate cancer. J Urol, 171: S36, 2004 Sung, S. Y. and Chung, L. W.: Prostate tumor-stroma interaction: molecular mechanisms and opportunities for therapeutic targeting. Differentiation, 70: 506, 2002 Clezardin, P.: Recent insights into the role of integrins in cancer metastasis. Cell Mol Life Sci, 54: 541, 1998 David Roodman, G.: Role of stromal-derived cytokines and growth factors in bone metastasis. Cancer, 97: 733, 2003 De Wever, O. and Mareel, M.: Role of tissue stroma in cancer cell invasion. J Pathol, 200: 429, 2003 Ball, E. M. and Risbridger, G. P.: New perspectives on growth factor-sex steroid interaction in the prostate. Cytokine Growth Factor Rev, 14: 5, 2003 Thiery, J. P.: Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer, 2: 442, 2002 Kang, Y. and Massague, J.: Epithelial-mesenchymal transitions: twist in development and metastasis. Cell, 118: 277, 2004 Liotta, L. A. and Kohn, E. C.: Stromal therapy: the next step in ovarian cancer treatment. J Natl Cancer Inst, 94: 1113, 2002 Chung, L. W., Hsieh, C. L., Law, A., Sung, S. Y., Gardner, T. A., Egawa, M. et al: New targets for therapy in prostate cancer: modulation of stromal-epithelial interactions. Urology, 62: 44, 2003 Matsubara, S., Wada, Y., Gardner, T. A., Egawa, M., Park, M. S., Hsieh, C. L. et al: A conditional replication-competent adenoviral vector, Ad-OC-E1a, to cotarget prostate cancer and bone
17.
18.
19.
20.
21. 22.
23.
stroma in an experimental model of androgen-independent prostate cancer bone metastasis. Cancer Res, 61: 6012, 2001 Tu, S. M., Millikan, R. E., Mengistu, B., Delpassand, E. S., Amato, R. J., Pagliaro, L. C. et al: Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial. Lancet, 357: 336, 2001 Rhee, H. W., Zhau, H. E., Pathak, S., Multani, A. S., Pennanen, S., Visakorpi, T. et al: Permanent phenotypic and genotypic changes of prostate cancer cells cultured in a threedimensional rotating-wall vessel. In Vitro Cell Dev Biol Anim, 37: 127, 2001 Pathak, S., Nemeth, M. A., Multani, A. S., Thalmann, G. N., von Eschenbach, A. C. and Chung, L. W.: Can cancer cells transform normal host cells into malignant cells? Br J Cancer, 76: 1134, 1997 Moinfar, F., Man, Y. G., Arnould, L., Bratthauer, G. L., Ratschek, M. and Tavassoli, F. A.: Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: implications for tumorigenesis. Cancer Res, 60: 2562, 2000 Paget, S.: The distribution of secondary growths in cancer of the breast. Lancet, 1: 571, 1889 Bissell, M. J., Radisky, D. C., Rizki, A., Weaver, V. M. and Petersen, O. W.: The organizing principle: microenvironmental influences in the normal and malignant breast. Differentiation, 70: 537, 2002 Ingber, D. E.: Cancer as a disease of epithelial-mesenchymal interactions and extracellular matrix regulation. Differentiation, 70: 547, 2002
Vol. 172, 2125–2126, December 2004 Printed in U.S.A.
DOI: 10.1097/01.ju.0000145136.48668.41
Editorials THE ROLES OF MYOFIBROBLASTS IN PROSTATE CARCINOGENESIS Cancer growth and differentiation are intimately affected by the cellular and host microenvironment. Much past investigation emphasized the diagnosis and treatment of cancer based on an understanding of the diseased epithelium alone. But cancer grows as a 3-dimensional organ surrounded by host stromal cells, and with time will manifest with different malignant potentials dependent on the genetic and epigenetic backgrounds of the host. There is an urgent need to understand how the cancer microenvironment differs from the benign or normal microenvironment and what factors determine the transition from a benign to a cancerous microenvironment. Ultimately the cancerous microenvironment should be considered an attractive therapeutic target because it can augment the growth, survival, invasion and metastasis of prostate cancer cells to the skeleton or soft tissues with or without continued evolution by the cancer cells. In this issue of The Journal Singh et al (page 2421) reveal evidence linking the reactive stroma with the tissue wound healing response and discuss possible roles in prostate carcinogenesis. In this and previous studies they have proposed that the reactive stroma has a dominant role in cancer growth and differentiation, possibly through the expression and specific signaling mediated by growth factors and extracellular matrices elaborated by cancer cells and/or the surrounding stroma.1–3 In this article the authors provide an attractive working hypothesis suggesting that the reactive stroma coevolves with prostate cancer under the control of transforming growth factor-1 (TGF-1). As the result of tumor-stroma interaction, TGF-1 could be the key candidate growth factor regulating the morphological conversion of normal stromal fibroblasts to a reactive stroma, or myofibroblasts. The important functional consequences include increased growth of cancer epithelium through decreased apoptosis as demonstrated in the results. The strengths of this experimental approach are the use of primary human prostate stromal and established human prostate cancer cell lines for the study, the successful demonstration of TGF-1 promotion of prostate stromal cells to undergo myofibroblastic transition in vitro, and the validation and documentation of the functional relationship between increased myofibroblast population and decreased prostate cancer epithelial apoptosis in prostate tumors grown in mice. The latter experimental observation emphasizes the importance of the possible direct interaction between myofibroblasts and prostate cancer cells, and downplays the mechanistic contribution of confounding factors such as host immune suppression or angiogenesis. This proposed concept is in accord with previous reports on the reciprocity of cellular communication between stroma and epithelium,4, 5 the contribution of inflammation to prostate cancer development,6 bidirectional cellular interaction between prostate cancer and prostate or bone stroma,7 and the surge in growth factors, inflammatory cytokines and extracellular matrice mediated signaling that accompanies cancer growth, development and progression.8 –11 It is also conceivable that interaction between cancer epithelium and the growth factor/extracellular matrix milieu surrounding the myofibroblasts could promote an epithelium to mesenchyme transition with enhanced cancer cell invasion, migration and metastasis.12, 13 The results of this study could have
important clinical implications and practical use in the future. By defining the stromal signature we may be able to predict the malignant status of future cancer cells. By evaluating gene expression rather than morphological changes associated with the transition of fibroblasts to myofibroblasts or epithelium to mesenchyme alone we may increase the sensitivity and specificity of prostate cancer diagnosis earlier and more accurately before morphological alterations could be recognized by pathologists. Gene profiling approaches could significantly complement the conventional histomorphological evaluation of pathological specimens under the microscope since stromal response, or dysmoplastic reaction, is infrequently observed in prostate cancer specimens. Understanding the cancer microenvironment interaction could also potentially affect cancer treatment. By exploring stroma targeting14 and by co-targeting stroma and epithelium,15 the survival of mice with prostate cancer xenografts grown in bone has been improved16 and the survival of patients with the lethal phenotype of hormonal refractory and bone metastatic disease has been improved.17 Tumor microenvironment interaction deserves further investigation. Remarkably, recent experimental evidence suggests that permanent genetic and gene expression changes occur in the stroma surrounding tumor epithelium in experimental models15, 18, 19 and in clinical specimens.20 Likewise the growth, invasion and colonization of cancer cells at different organ sites and the genetics of cancer cells are also affected by host organ microenvironment.21–23 This supports the coevolutionary concept proposed by Singh et al and confirms a long held fear that cancer and stroma are moving targets that can only be effectively attacked by a combination therapy covering a broad spectrum of overlapping and clonally specific targets. To move this field forward we need to expand our current knowledge of stromal molecular biology from cell cultures to live animals, with specific emphasis on biologically and clinically relevant cancer-stroma interaction targets and models. Such investigations will lead to improved applications benefiting patients in the clinic.
2125
Leland W. K. Chung Department of Urology Molecular Urology and Therapeutics Program and Winship Cancer Institute Emory University School of Medicine Atlanta, Georgia 1. Tuxhorn, J. A., McAlhany, S. J., Yang, F., Tang, T. D. and Rowley, D. R.: Inhibition of transforming growth factor-beta activity decreases angiogenesis in a human prostate cancerreactive stroma xenograft model. Cancer Res, 62: 6021, 2002 2. Rowley, D. R.: What might a stromal response mean to prostate cancer progression? Cancer Metastasis Rev, 17: 411, 1998 3. Gerdes, M. J., Larsen, M., Dang, T. D., Ressler, S. J., Tuxhorn, J. A. and Rowley, D. R.: Regulation of rat prostate stromal cell myodifferentiation by androgen and TGF-beta1. Prostate, 58: 299, 2004 4. Lelievre, S. A., Weaver, V. M., Nickerson, J. A., Larabell, C. A., Bhaumik, A., Petersen, O. W. et al: Tissue phenotype depends on reciprocal interaction between the extracellular matrix and the structural organization of the nucleus. Proc Natl Acad Sci USA, 95: 14711, 1998 5. Chung, L. W., Gleave, M. E., Hsieh, J. T., Hong, S. J. and Zhan, H. E.: Reciprocal mesenchymal-epithelial interaction affecting
2126
6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
16.
MYOFIBROBLASTS IN PROSTATE CARCINOGENESIS
prostate tumour growth and hormonal responsiveness. Cancer Surv, 11: 91, 1991 Platz, E. A. and De Marzo, A. M.: Epidemiology of inflammation and prostate cancer. J Urol, 171: S36, 2004 Sung, S. Y. and Chung, L. W.: Prostate tumor-stroma interaction: molecular mechanisms and opportunities for therapeutic targeting. Differentiation, 70: 506, 2002 Clezardin, P.: Recent insights into the role of integrins in cancer metastasis. Cell Mol Life Sci, 54: 541, 1998 David Roodman, G.: Role of stromal-derived cytokines and growth factors in bone metastasis. Cancer, 97: 733, 2003 De Wever, O. and Mareel, M.: Role of tissue stroma in cancer cell invasion. J Pathol, 200: 429, 2003 Ball, E. M. and Risbridger, G. P.: New perspectives on growth factor-sex steroid interaction in the prostate. Cytokine Growth Factor Rev, 14: 5, 2003 Thiery, J. P.: Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer, 2: 442, 2002 Kang, Y. and Massague, J.: Epithelial-mesenchymal transitions: twist in development and metastasis. Cell, 118: 277, 2004 Liotta, L. A. and Kohn, E. C.: Stromal therapy: the next step in ovarian cancer treatment. J Natl Cancer Inst, 94: 1113, 2002 Chung, L. W., Hsieh, C. L., Law, A., Sung, S. Y., Gardner, T. A., Egawa, M. et al: New targets for therapy in prostate cancer: modulation of stromal-epithelial interactions. Urology, 62: 44, 2003 Matsubara, S., Wada, Y., Gardner, T. A., Egawa, M., Park, M. S., Hsieh, C. L. et al: A conditional replication-competent adenoviral vector, Ad-OC-E1a, to cotarget prostate cancer and bone
17.
18.
19.
20.
21. 22.
23.
stroma in an experimental model of androgen-independent prostate cancer bone metastasis. Cancer Res, 61: 6012, 2001 Tu, S. M., Millikan, R. E., Mengistu, B., Delpassand, E. S., Amato, R. J., Pagliaro, L. C. et al: Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial. Lancet, 357: 336, 2001 Rhee, H. W., Zhau, H. E., Pathak, S., Multani, A. S., Pennanen, S., Visakorpi, T. et al: Permanent phenotypic and genotypic changes of prostate cancer cells cultured in a threedimensional rotating-wall vessel. In Vitro Cell Dev Biol Anim, 37: 127, 2001 Pathak, S., Nemeth, M. A., Multani, A. S., Thalmann, G. N., von Eschenbach, A. C. and Chung, L. W.: Can cancer cells transform normal host cells into malignant cells? Br J Cancer, 76: 1134, 1997 Moinfar, F., Man, Y. G., Arnould, L., Bratthauer, G. L., Ratschek, M. and Tavassoli, F. A.: Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: implications for tumorigenesis. Cancer Res, 60: 2562, 2000 Paget, S.: The distribution of secondary growths in cancer of the breast. Lancet, 1: 571, 1889 Bissell, M. J., Radisky, D. C., Rizki, A., Weaver, V. M. and Petersen, O. W.: The organizing principle: microenvironmental influences in the normal and malignant breast. Differentiation, 70: 537, 2002 Ingber, D. E.: Cancer as a disease of epithelial-mesenchymal interactions and extracellular matrix regulation. Differentiation, 70: 547, 2002