Abstract
Simple SummaryDespite recent advances in the therapeutic management of metastasized prostate cancer, disease progression is still inevitable, with often fatal outcomes. Elucidating molecular mechanisms crucial to cancer development and progression is therefore necessary to find ways to interfere in metastatic processes and ultimately improve prognosis. Since soluble (s)E-cadherin is elevated in the serum of patients with prostate cancer, we investigated its influence on prostate cancer cell behavior in vitro. Exposure to sE-cadherin increased the systemic spread of the cells. Thus, targeting sE-cadherin might be a novel and innovative concept to treat advanced PCa.The serum level of soluble (s)E-cadherin is elevated in several malignancies, including prostate cancer (PCa). This study was designed to investigate the effects of sE-cadherin on the behavior of PCa cells in vitro, with the aim of identifying a potential therapeutic target. Growth as well as adhesive and motile behavior were evaluated in PC3, DU-145, and LNCaP cells. Flow cytometry was used to assess cell cycle phases and the surface expression of CD44 variants as well as α and β integrins. Confocal microscopy was utilized to visualize the distribution of CD44 variants within the cells. Western blot was applied to investigate expression of α3 and β1 integrins as well as cytoskeletal and adhesion proteins. Cell growth was significantly inhibited after exposure to 5 µg/mL sE-cadherin and was accompanied by a G0/G1-phase arrest. Adhesion of cells to collagen and fibronectin was mitigated, while motility was augmented. CD44v4, v5, and v7 expression was elevated while α3 and β1 integrins were attenuated. Blocking integrin α3 reduced cell growth and adhesion to collagen but increased motility. sE-cadherin therefore appears to foster invasive tumor cell behavior, and targeting it might serve as a novel and innovative concept to treat advanced PCa.
Highlights
Despite the widespread use of prostate-specific antigen (PSA)-based screening together with steadily evolving molecular imaging and theranostics, morbidity and mortality due to prostate cancer (PCa) remain a significant burden to the male population
We have previously demonstrated that soluble (s) E-cadherin is overexpressed in the serum of patients with PCa and renal cell carcinoma (RCC) [7,8]
Since the serum concentration of sE-cadherin has been reported to be upregulated in patients with several cancers including PCa [7,8,12,13], we aimed to explore the impact of sE-cadherin on PCa cell growth and invasive behavior
Summary
Despite the widespread use of prostate-specific antigen (PSA)-based screening together with steadily evolving molecular imaging and theranostics, morbidity and mortality due to prostate cancer (PCa) remain a significant burden to the male population. A contemporary analysis using the GLOBOCAN 2020 database estimated PCa to be the second leading malignancy and the fifth most common cause of cancer-related death in men worldwide, numbering 1,414,259 and 375,304 cases, respectively [1]. Global incidence and mortality rates of PCa based on the GLOBOCAN 2018 database have stabilized in most countries over the previous 5 years [2]. While localized PCa can be curatively managed by radiotherapy or radical prostatectomy, metastatic disease most often results in mortality. Advanced castration-resistant PCa clinical disease management has been improved by employing Poly (ADP-ribose) polymerase (PARP) inhibitors in men with BRCA1 or BRCA2 mutations together with radioligand therapy with Lutetium-177 (177Lu)-PSMA-617 [5]
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