Focal degeneration of basal cells and the resultant auto-immunoreactions: a novel mechanism for prostate tumor progression and invasion.
The development of human prostate cancer is believed to be a multistep process, progressing sequentially from normal, to hyperplasia, to prostatic intraepithelial neoplasia (PIN), and to invasive and metastatic lesions. High grade PIN has been generally considered as the direct precursor of invasive lesions, and the progression of PIN is believed to be triggered primarily, if not solely, by the overproduction of proteolytic enzymes predominately by cancer cells, which result in the degradation of the basement membrane. These theories, however, are hard to reconcile with two main facts: (1) only about 30% untreated PIN progress to invasive stage, while none of the current approaches could accurately identify the specific PIN or individuals at greater risk for progression, and (2) results from recent world-wide clinical trials with a wide variety of proteolytic enzyme inhibitors have been very disappointing, casting doubt on the validity of the proteolytic enzyme theory. Since over 90% of prostate cancer-related deaths result from invasion-related illness and the incidence of PIN could be up to 16.5-25% in routine or ultrasound guided prostate biopsy, there is an urgent need to uncover the intrinsic mechanism of prostate tumor invasion. Promoted by the facts that the basal cell population is the source of several tumor suppressors and the absence of the basal cell layer is the most distinct feature of invasive lesions, our recent studies have intended to identify the early alterations of basal cell layers and their impact on tumor invasion using multidisciplinary approaches. Our studies revealed that a subset of pre-invasive tumors contained focal disruptions (the absence of basal cells resulting in a gap greater than the combined size of at least three epithelial cells) in surrounding basal cell layers. Compared to their non-disrupted counterparts, focally disrupted basal cell layers had several unique features: (1) significantly lower proliferation; (2) significantly lower p63 expression; (3) significantly higher apoptosis; and (4) significantly higher leukocyte infiltration and stromal reactions. Compared to their counterparts distant from focal disruptions or overlying non-disrupted basal cell layers, epithelial cells overlying focal basal cell layer disruptions showed the following unique features: (1) significantly higher proliferation; (2) significantly higher expression of cell cycle control-, cell growth-, and stem cell-related genes; and (3) physical continuity with adjacent invasive lesions. Together, these findings suggest that focal basal cell layer disruptions could substantially impact the molecular profile and biological presentations of the overlying epithelial cells. Based on these and other findings, we have proposed that prostate tumor invasion is triggered by a localized degeneration of aged or injured basal cells and the resultant auto-immunoreactions. Our hypothesized steps for prostate tumor invasion include the following: (1) due to inherited or environmental factors, some patients contained cell cycle control- and renewal-related defects in the basal cell population that cause elevated basal cell degenerations; (2) the degradation products of degenerated basal cells or diffusible molecules of the overlying epithelial cells attract leukocyte infiltration; (3) leukocytes discharge their digestive enzymes upon the direct physical contact, resulting in a focal disruption in the basal cell layer, which leads to several focal alterations: (a) a focal loss of tumor suppressors and paracrine inhibitory function; (b) a focal increase of the permeability for growth-required nutrients and oxygen; (c) a focal increase of growth factors; (d) direct physical contact between epithelial and stromal cells; and (e) the exposure of the overlying epithelial cells directly to the stromal tissue fluid. These alterations individually or collectively stimulate or favor a clonal proliferation and stromal invasion of tumor progenitor or stem cells. Our hypothesis differs from the traditional theories in several aspects, including the triggering factor for the initiation of tumor invasion, the stage of tumor invasion, the cellular origin of invasive lesions, the significance of immunoreactive and stromal cells, and the potential approaches for early detection, treatment, and prevention of invasion. Our hypothesis represents a novel in vivo model as to the cellular mechanism leading to prostate tumor invasion. If confirmed, it could lead to a new direction to search for more effective approaches to combat prostate cancer. It could also have an immediate impact on patient care through improved pathologic evaluation of prostate tumor biopsies. More importantly, our hypothesis might be applicable, and significantly impact the detection, treatment, and prevention of other epithelium-derived tumors.
American Registry of Pathology and Armed Forces Institute of Pathology, 6825 16th Street, NW, Washington, DC 20306-6000, USA. man@afip.osd.mil <man@afip.osd.mil>
Yan-Gao
YG
Man
William A
WA
Gardner
D015551:Autoimmunity; D049109:Cell Proliferation; D015870:Gene Expression; D006801:Humans; D007962:Leukocytes / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D018448:Models, Immunological; D009361:Neoplasm Invasiveness / Q000276:immunology / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D019048:Prostatic Intraepithelial Neoplasia / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000209:etiology / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D017154:Stromal Cells / Q000473:pathology; D019063:Tenascin / Q000378:metabolism
C081876:CKAP4 protein, human; D008565:Membrane Proteins; D018809:Proliferating Cell Nuclear Antigen; D019063:Tenascin