Is tissue mass regulated by vascular endothelial cells? Prostate as the first evidence

J Folkman - Endocrinology, 1998 - academic.oup.com
J Folkman
Endocrinology, 1998academic.oup.com
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 …
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), insulinlike 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 In unpublished data from the authors’ laboratory (Häggström et al.), castration decreased and testosterone increased vascular endothelial growth factor (VEGF) mRNA expression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). There-
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