Trop-2 is up-regulated in invasive prostate cancer and displaces FAK from focal contacts

Abstract

In this study, we show that the transmembrane glycoprotein Trop-2 is up-regulated in human prostate cancer (PCa) with extracapsular extension (stages pT3/pT4) as compared to organ-confined (stage pT2) PCa. Consistent with this evidence, Trop-2 expression is found to be increased in metastatic prostate tumors of Transgenic Adenocarcinoma of Mouse Prostate mice and to strongly correlate with α5β1 integrin levels. Using PCa cells, we show that Trop-2 specifically associates with the α5 integrin subunit, as binding to α3 is not observed, and that Trop-2 displaces focal adhesion kinase from focal contacts. In support of the role of Trop-2 as a promoter of PCa metastatic phenotype, we observe high expression of this molecule in exosomes purified from Trop-2-positive PCa cells. These vesicles are then found to promote migration of Trop-2-negative PCa cells on fibronectin, an α5β1 integrin/focal adhesion kinase substrate, thus suggesting that the biological function of Trop-2 may be propagated to recipient cells. In summary, our findings show that Trop-2 promotes an α5β1 integrin-dependent pro-metastatic signaling pathway in PCa cells and that the altered expression of Trop-2 may be utilized for early identification of capsule-invading PCa.

Laminin γ2‐enriched extracellular vesicles of oral squamous cell carcinoma cells enhance in vitro lymphangiogenesis via integrin α3‐dependent uptake by lymphatic endothelial cells

“…Of these, several are differentially expressed in certain stages and types of cancers and may be used as diagnostic markers of cancer progression. For example, the tumor‐associated calcium signal transducer 2 was uniquely expressed in prostate cancers in a late stage in comparison with early‐stage prostate cancerous tissues . In our study, laminin α3, β3 and γ2 have been identified as upregulated proteins in LN1‐1 EVs (Figs.…”

v-Src Oncogene Induces Trop2 Proteolytic Activation via Cyclin D1

“…Trop2 associates with the α5 integrin subunit, and thereby displaces focal adhesion kinase from focal contacts to promote an invasive phenotype. Consistent with this finding, Trop2 is up-regulated in human prostate cancer (PCa) with extracapsular extension (stages pT3/pT4) as compared to organ-confined (stage pT2) PCa (14-16). Intramembrane proteolysis of Trop2 occurs by the TNFα converting enzyme (TACE) then by γ-secretase.…”

“…1C). In recent studies Trop2, which is known to be expressed in a subpopulation of prostate basal cells with stem cell characteristics, was shown to correlate with poor prognosis in prostate cancer (11,16,29). Trop2 is activated by RIP (regulated intra-membrane proteolysis), a mechanism involved in processing and activation of other transmembrane proteins, including N-cadherin and E-cadherin (30).…”

“…Trop2 has oncogenic activity (12) demonstrated by chimeric cyclin D1-Trop2 fusions in many cancer types, and silencing the fusion protein inhibits tumor growth (13). The related Trop2 family member, EpCAM, is considered a therapeutic target through regulation of cell-cell adhesion (14-16). Trop2 associates with the α5 integrin subunit, and thereby displaces focal adhesion kinase from focal contacts to promote an invasive phenotype.…”

Prognostic and predictive biomarkers of prostate cancer

“…Уровень TROP2 / TACSTD2 повышен ОНКОУРОЛОГИЯ 4'2017 ТОМ 13 CANCER UROLOGY 4'2017 VOL. 13 118 Обзоры при распространенном РПЖ (стадии pT3 / pT4) по сравнению с локализованным (стадия pT2) [45]. Для Src-киназной индукции ядерного накопления TACSTD2 требуется циклин D1.…”