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Editorial: Is Tissue Mass Regulated by Vascular Endothelial Cells? Prostate as the First Evidence

Children’s Hospital and Harvard Medical School Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Judah Folkman, M.D., Harvard Medical School, Children’s Hospital, Department of Anatomy and Cell Biology, 300 Longwood, Boston, Massachusetts 02115-5737.

	Introduction

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There is now considerable direct evidence that tumor growth is angiogenesis dependent, and that tumor mass is under the tight control of microvascular endothelium (1). New capillary vessels recruited by tumors carry nutrients and oxygen into a tumor and remove catabolites and carbon dioxide from it. This perfusion effect is however, reinforced by a potent paracrine effect. Microvascular endothelial cells release into their extracellular matrix and into the tumor itself a variety of growth and survival factors (2, 3). At least twenty such endothelial-derived paracrine factors are known (3), but those that have been studied in most detail include: basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1), heparin-binding epithelial growth factor and interleukin-6.

Whether organ size or normal tissue mass is under the control of vascular endothelium has remained an open question. In this issue, Franck-Lissbrant et al. (4) show that growth of the rat prostate gland is regulated by vascular endothelial cells, which themselves are apparently responding to angiogenic activity elaborated by prostate epithelium under testosterone stimulation. The elegant experiments in this report demonstrate that testosterone stimulation in castrated rats causes the rapid onset of a wave of endothelial cell proliferation and vessel growth which is increased 3-fold in the first day and normalizes by 2 days. This burst of endothelial cell growth precedes by several days regrowth of glandular epithelium and subsequent enlargement of prostate mass. In unpublished data from the authors’ laboratory (Häggström et al.), castration decreased and testosterone increased vascular endothelial growth factor (VEGF) mRNA expression in the prostate.

This is a seminal paper because it: 1) reports the first compelling evidence that normal tissue mass (including organ size) is tightly regulated by vascular endothelium; and 2) demonstrates a molecular pathway by which steroid hormones can mediate production of angiogenic peptides. This connection of male reproductive steroid hormones to angiogenic proteins may also hold for female reproductive steroids. For example, estradiol treatment of human endometrial cells increased expression of VEGF mRNA by 3-fold (5). Franck-Lissbrant et al. (4) also found that macrophages increased in the prostate after castration and returned to intact values after testosterone treatment. Macrophages could be a source of an angiogenesis inhibitor, angiostatin (6), which can be liberated from plasminogen by macrophage-derived metalloelastase (7). Therefore, as the authors suggest, the growth or regression of microvasculature in the prostate may be the result of a net balance of positive and negative regulators of angiogenesis, as has been demonstrated in tumors (8). Macrophages are also a source of an angiogenic stimulator, VEGF. In fact, VEGF secretion by macrophages in human endometriosis is increased in response to ovarian steroids (9). This steroid regulation of angiogenic proteins represents another similarity between the male and female reproductive systems.

A study in our own laboratory (10) of hormone-responsive human prostate carcinoma confirms the results of Franck-Lissbrant et al. (4) in normal prostate. Androgen deprivation of human prostate carcinoma cells (LnCap) in vitro led to a marked decrease in VEGF mRNA expression. In addition, androgen withdrawal inhibited the hypoxic induction of VEGF. In mice bearing human prostate carcinomas, castration resulted in a rapid decrease in VEGF expression within 24 h and a marked reduction in neovascularization by 3 days. Tumor regression did not begin until 8 days, demonstrating that inhibition of vascular endothelial growth precedes reduction in tumor mass. It remains to be determined whether escape of prostate carcinoma to androgen-independence is associated with overexpression of VEGF by the tumor cells.

When angiogenesis is blocked in tumors by specific inhibitors of endothelial proliferation such as angiostatin (11) or endostatin (12), there is an increase in tumor cell apoptosis, with no change in the elevated rate of tumor cell proliferation, suggesting that tumor cells may become apoptotic following withdrawal of endothelial-derived growth and survival factors. It has been shown in certain tumors that one endothelial cell supports 5 to 50 tumors cells (13). If normal cells are similarly dependent upon endothelial-derived paracrine factors, the ratio of endothelial cells to normal parenchymal cells is likely to be lower than for tumor cells. Nevertheless, the regulation of tissue mass or organ size by vascular endothelial cells may be based upon mechanisms which also operate in tumors.

The report by Franck-Lissbrant et al. (4) has broad implications for our understanding of the role of vascular endothelium in embryonic development and wound repair as well as in physiological involution or hypertrophy of normal organs. If the mechanism of endothelial control of prostate size as reported here can be generalized to other tissues, it may lead to the discovery of endothelial-derived growth or survival factors that are critical for different organs, for example, liver and kidney (Fig. 1).

View larger version (24K): [in this window] [in a new window]   Figure 1. Diagram to illustrate a proposed general mechanism by which normal tissue mass may be regulated by the paracrine effect of microvascular endothelial cells (the perfusion effect of neovascularization is not shown). A similar principle could apply to ovary, liver, or other organs.

Received November 26, 1997.

	References

Top Introduction References

 

1. Folkman J 1997 Cancer: Principles & Practice of Oncology, ed. 5. Lippincott-Raven Publishers, pp 3075–3085
2. Hamada J, Cavanaugh PG, Lotan O, Nicolson GL 1992 Separable growth and migration factors for large-cell lymphoma cells secreted by microvascular endothelial cells derived from target organs for metastasis. Br J Cancer 66:349–354[Medline]
3. Rak J, Filmus J, Kerbel RS 1996 Reciprocal paracrine interactions between tumour cells and endothelial cells: the ‘angiogenesis progression’ hypothesis. Eur J Cancer 32A:2438–2450
4. Franck-Lissbrant I, Häggström S, Damber J-E, Bergh A 1998 Testosterone stimulates angiogenesis and vascular regrowth in the ventral prostate in castrated rats. Endocrinology 139:451–456[Abstract/Free Full Text]
5. Shifren JL, Tseng JF, Zaloudek CJ, Ryan IP, Meng YG, Ferrara N, Jaffe RB, Taylor 1996 Ovarian steroid regulation of vascular endothelial growth factor in human endometrium: implications for angiogenesis during the menstrual cycle and in the pathogenesis of endometriosis. J Clin Endocrinol Metab 81:3112–3118[Abstract/Free Full Text]
6. O’Reilly MS, Holmgren L, Shing Y, Chen C, Rosenthal RA, Moses M, Lane WS, Sage EH, Folkman J 1994 Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79:325–328
7. Dong Z, Kumar R, Yang X, Fidler IJ 1997 Macrophage-derived metalloelastase is responsible for the generation of angiostatin in Lewis luing carcinoma. Cell 88:801–810[CrossRef][Medline]
8. Hanahan D, Folkman J 1996 Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364[CrossRef][Medline]
9. McLaren J, Prentice A, Charnock-Jones DS, Millican SA, Muller KH, Sharkey AM, Smith SK 1996 Vascular endothelial growth factor is produced by peritoneal fluid macrophages in endometriosis and is regulated by ovarian steroids. J Clin Invest 98:482–489[Medline]
10. Stewart RJ, Pangraphy D, Flynn E, Folkman J Vascular endothelial growth factor expression and tumor angiogenesis is regulated by androgens in hormone-responsive human prostate carcinoma. (submitted for publication)
11. Holmgren L, O’Reilly MS, Folkman J 1995 Dormancy of micrometastases: Balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nature Med 1:149–153[CrossRef][Medline]
12. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, Flynn E, Birkhead JR, Olsen BR, Folkman J 1997 Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88:277–285[CrossRef][Medline]
13. Modzelewski RA, Davies P, Watkins SC, Auerbach R, Chang M-J, Johnson CS 1994 Isolation and identification of fresh tumor-derived endothelial cells from a murine RIF-1 fibrosarcoma. Cancer Res 54:336–339[Abstract/Free Full Text]

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