Malignant Transformation and Stromal Invasion from Normal Appearing Prostate Tissues: True or False?

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The human prostate epithelium, which is the histological origin of most prostate malignancies, is physically separated from the stroma by a layer of basal cells and the basement membrane. Basal cells are inter-connected by intercellular junctions and adhesion molecules, constituting a continuous sheet encircling luminal cells [1-2]. The basement membrane is composed of type IV collagen, laminins, and other molecules, forming a continuous lining surrounding and attaching to the basal cell layer [3-4] (Fig 1). The basement membrane and the basal cell layer are intermixed to form a dense fibrous capsule surrounding all epithelial cells. Due to these relationships, disruption of the basal cell layer and the basement membrane is a pre-requisite for tumor invasion or metastasis. It is a commonly held belief that prostate carcinogenesis progresses sequentially from normal to hyperplasia, to prostatic intraepithelial neoplasia (PIN), and to invasive or metastatic lesions [5-8]. Progression from PIN to invasion is believed to be triggered by overproduction of proteolytic enzymes primarily by cancer cells, which cause degradation of the tumor capsule [9-10]. These theories are consistent with laboratory findings from cell cultures and animal models, whereas are hard to reconcile with a number of critical facts. First, previous studies revealed that some healthy men between 19 and 29 years old had a spectrum of proliferative lesions, including hyperplasia, PIN, and incipient adenocarcinoma [11-13]. Second, recent studies have detected a DNA phenotype identical to that of invasive prostate cancer in some “healthy” men, and also in normal prostate tissues adjacent to prostate cancer [14-17]. Third, a majority of PIN express high levels of proteolytic enzymes, but only 10-30% of untreated PIN progress to invasive lesions during patients’ lifetime [1821]. Fourth, cancer of unknown primary site is one of the 10 most frequent cancers worldwide and the 4th most common cause of cancer deaths [22-24]. Together, these facts argue that the linear model of carcinogenesis [5-8] and enzyme theory of tumor invasion [9-10] are not universally applicable to all prostate cancer cases. These facts also suggest that the past efforts to classify tumor progression and invasion purely based on the profiles of epithelial cells may have overlooked some essential factors. As over 90% of prostate cancer related mortality result from invasion related diseases, and the incidence of PIN could be up to 16.5%-25% in prostate biopsies [25-27], there is an urgent