Intercellular Communication and Human Prostate Carcinogenesis

Abstract

Gap‐junction‐mediated intercellular communication (GJIC) is required for completion of embryonic development, tissue homeostasis, and regulation of cell proliferation and death. Although, as emphasized in several reports, defects or disruption of GJIC may be important in carcinogenesis, the potential role of GJIC in the onset and progression of human prostate cancer remains ill‐defined. The gap junction channel‐forming connexins (Cx) comprise a multigene family of highly conserved proteins that are differentially expressed in a tissue‐ and development‐specific manner; changes in connexin expression are also commonly seen during cellular differentiation. However, when multiple connexins are concurrently expressed, gap junction channels may consist of more than one connexin species. This is important, because only certain pairings give rise to functional channels. In our studies, we investigated GJIC in a panel of both nontumorigenic (RWPE‐1) and malignant (RWPE‐2, LNCaP, DU‐145) human prostate epithelial cells, compared to a normal rat liver epithelial F344 (WB‐1) cell line, as it was found to be junctionally proficient. In addition, expression and regulation of Cx43 and Cx32 were also inspected using western blot analysis. The ability of hormones, antihormones, and the antihypertensive drug forskolin to restore GJIC in nontumorigenic and malignant human prostate epithelial cells was examined by the scrape‐loading/dye transfer (SL/DT) or fluorescence recovery after photobleaching (FRAP) methods using an Ultima laser cytometer. Results from both assays showed that neither nontumorigenic nor malignant prostate cells have functional GJIC. However, both estrone (E1) and forskolin (FK) induced a significant increase (4.4‐ and 2.8‐fold, respectively) in cell‐cell communication only in the RWPE‐1 cells. Interestingly, the use of Matrigel, a solubilized basement membrane, as substrate for cell attachment and growth resulted in the rescue of GJIC activity in RWPE‐1 cells, as revealed by the SL/DT method. Furthermore, E1 induced a twofold increase in connexin 43 (Cx43), whereas forskolin caused a 50% reduction in Cx32 expression in RWPE‐1 cells. These data suggest that agents that increase Cx43:Cx32 ratio may restore GJIC in junctionally deficient cells, providing a basis for the development of new strategies for the prevention and treatment of human prostate cancer.

Prognostic value of connexin43 expression in patients with clinically localized prostate cancer

“…2,7 Cxs are differentially expressed in cell and tissue in developmentally specific manner. 8 The expression of some Cxs is altered and often reduced during tumour progression. 2 Forced expression of Cxs genes in communication-deficient tumour cells retards growth, reduces tumourigenicity and induces differentiation.…”

XIAP as a Molecular Target for Therapeutic Intervention in Prostate Cancer

“…Promoted by the reports that: [1] basal cells are the source of several tumor suppressors, including p63 and maspin, [2] the absence of basal cell layer is the most distinct feature of invasive lesions, and [3] chronic inflammation promotes prostate cancer (14)(15)(16)(17)(18), our recent studies have attempted to identify the early alterations of basal cell layers and their potential impact on prostate tumor invasion. Using a double ummunostaining method with antibodies to cytokeratin (CK) 34ßE12 (a basal cell phenotypic marker), our initial study assessed the physical integrity of basal call layers in paraffin-embedded tumor (n=50) prostate tissues with co-existing pre-invasive and invasive components (19).…”

“…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 localized loss of tumor suppressors and paracrine inhibitory function, which confers tumor cell growth advantages to escape the programmed cell death (21-25).…”

A seemingly most effective target for early detection and intervention of prostate tumor invasion

“…The basement membrane is composed of type IV collagen, laminins, and other molecules, forming a continuous lining surrounding the basal cell layer [3][4] (Fig 1). Together, the basal cell layer and the basement membrane constitute a morphologically distinct capsule, which is a permanent structural element largely independent of hormonal regulation and the host's bio-physiological condition [1][2][3][4]. The epithelial cells are held in place by intercellular junctions and cell surface adhesion molecules (Fig 2).…”

“…Basal cells are joined by intercellular junctions and cell surface adhesion molecules, forming a largely continuous sheet encircling epithelial cells [1][2]. The basement membrane is composed of type IV collagen, laminins, and other molecules, forming a continuous lining surrounding the basal cell layer [3][4] (Fig 1).…”