ReviewThe role of the stromal microenvironment in prostate cancer
Introduction
Cancer of the prostate is, by far, the most frequently diagnosed cancer in American males and the second leading cause of cancer deaths in this population. The American Cancer Society estimates that more than 230,000 new cases of prostate cancer will be diagnosed, and that 29,900 men will die from the disease in the United States in 2004 [1]. Small, clinically undetectable prostate malignancies (“histologic prostate cancer”) are even more common [2], [3]. Although clinical prostate cancer and prostate cancer mortality rates are much higher in Western countries than in Asian or African countries, histologic prostate carcinomas are almost as frequent [4]. Thus, the progression of prostate cancer from histologic cancer to clinically detectable and metastasizing cancer is of clear importance. Several recent studies in this field have focused on the role of stromal cells in the processes of progression and metastasis, and it is evident that key phenotypic changes in progressing prostate cancer cells are critically modulated by a dynamic, two-way communication between these cells and various stromal cells, including fibroblasts, smooth muscle cells, vascular endothelium, and bone-derived cells, including osteoblasts [5], [6], [7], [8], [9], [10]. This article will provide an overview of the significance of the stromal microenvironment to selected aspects of prostate carcinogenesis.
Section snippets
Development and maintenance of the normal prostate
The adult human prostate is a compact organ situated at the neck of the urinary bladder and surrounding the urethra. It is enclosed in a thin fibrous capsule and its parenchyma consists of numerous branching tubuloalveolar glands terminating in ducts that ultimately empty into the urethra. Histologically, each glandular acinus is lined with secretory (typically cuboidal to columnar) luminal epithelial cells and a discontinuous layer of basal cells and is embedded in a fibromuscular stroma.
The
Epithelial responses to prostate stroma during prostate carcinogenesis
Both androgens and estrogens influence the process of prostate carcinogenesis [25]. For example, recent studies show that, in hypogonadal, androgen-deficient male mice, exogenous estradiol stimulates prostatic cell proliferation [26]. Furthermore, in aromatase knockout, estrogen-deficient male mice, elevated androgen levels induce prostatic hyperplasia [27]. No malignant changes were detected in either case. However, combined androgen and estrogen treatment is capable of evoking prostatic
Angiogenesis
Thanks to the pioneering work of Judah Folkman, angiogenesis is now recognized as a significant event in tumor progression and in the acquisition of the malignant phenotype [33], [34]. In an attempt to support their own metabolic needs, malignant tumors typically induce neovascularization of themselves by evoking the influx of endothelial cells. These cells, in turn, proliferate and differentiate into new blood vessels. The mechanisms which control these events in prostate carcinogenesis have
Metastasis to bone
The clinical fate of a prostate cancer patient is ultimately determined by the primary tumor's capacity to grow, invade locally, evoke angiogenesis, and, eventually, metastasize. Most commonly, human prostate carcinomas metastasize to bone [45], [46]. This aspect of prostate cancer progression is both widespread and clinically critical; this is highlighted by the finding that at least 80% of prostate cancers demonstrate osseous micrometastases [47]. Unfortunately, the mechanisms responsible for
Summary
Evidence suggests that the cellular and acellular microenvironment of a prostate cancer cell critically influences its ability to survive, invade, evoke angiogenesis, and form secondary tumors. Though some of the steps involved in these events have been well characterized in both in vivo and in vitro models, specific mechanisms of the cancer cell with its environment are still poorly understood. Several researchers, most notably Leland Chung, have emphasized the importance of elucidating the
Acknowledgements
The author gratefully acknowledges Dr. Maarten Bosland for critical reading of the manuscript and helpful suggestions. This work was supported in part by NIH grants CA76426, CA75293, and CA 104334, and NIH Center Grants CA13343 and ES00260.
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