Tspan8 is expressed in breast cancer and regulates E‐cadherin/catenin signalling and metastasis accompanied by increased circulating extracellular vesicles

Abstract

Tspan8 exhibits a functional role in many cancer types including pancreatic, colorectal, oesophagus carcinoma, and melanoma. We present a first study on the expression and function of Tspan8 in breast cancer. Tspan8 protein was present in the majority of human primary breast cancer lesions and metastases in the brain, bone, lung, and liver. In a syngeneic rat breast cancer model, Tspan8+ tumours formed multiple liver and spleen metastases, while Tspan8− tumours exhibited a significantly diminished ability to metastasise, indicating a role of Tspan8 in metastases. Addressing the underlying molecular mechanisms, we discovered that Tspan8 can mediate up‐regulation of E‐cadherin and down‐regulation of Twist, p120‐catenin, and β‐catenin target genes accompanied by the change of cell phenotype, resembling the mesenchymal–epithelial transition. Furthermore, Tspan8+ cells exhibited enhanced cell–cell adhesion, diminished motility, and decreased sensitivity to irradiation. As a regulator of the content and function of extracellular vesicles (EVs), Tspan8 mediated a several‐fold increase in EV number in cell culture and the circulation of tumour‐bearing animals. We observed increased protein levels of E‐cadherin and p120‐catenin in these EVs; furthermore, Tspan8 and p120‐catenin were co‐immunoprecipitated, indicating that they may interact with each other. Altogether, our findings show the presence of Tspan8 in breast cancer primary lesion and metastases and indicate its role as a regulator of cell behaviour and EV release in breast cancer. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Extracellular vesicle tetraspanin-8 level predicts distant metastasis in non–small cell lung cancer after concurrent chemoradiation

“…We hypothesized that EVs secreted by metastatic and nonmetastatic NSCLC cells carry proteins that can distinguish these cells and function as diagnostic biomarkers of metastatic NSCLC. To test this hypothesis, we used mass spectrometry (MS) to detect EV proteins that were differentially expressed in two mouse NSCLC cell lines with metastatic and nonmetastatic phenotypes and found that EV expression of tetraspanin-8 (Tspan8) was associated with NSCLC invasiveness, in keeping with findings that its elevated cellular expression is associated with metastasis (10)(11)(12). Subsequent analysis found that intersectin-2 (Itsn2) expression, which regulates Tspan8 packaging into EVs (13,14), was increased in the metastatic NSCLC cell line and that overexpression of Itsn2 increased EV Tspan8 abundance and EV-enhanced NSCLC cell invasion.…”

TSPAN8 as a Novel Emerging Therapeutic Target in Cancer for Monoclonal Antibody Therapy

“…TSPAN8 protein is present in the majority of human primary breast cancer lesions and metastases in different organs (the brain, bone, lung and liver). TSPAN8 enhances cell-cell adhesion, proliferation, mesenchymal-epithelial transition, radiation resistance and extracellular vesicle release [78].…”

Utilização de mineração de dados para avaliar perfis de expressão e potencial valor prognóstico de genes identificados em tumores de mama triplo negativo com expressão diferencial do SPARC (Secreted Protein Acidic Rich in Cisteine)

“…Evidências crescentes sugerem que o TSPAN8 promove a migração, invasão e metástase de células tumorais em vários tipos de câncer humano, incluindo câncer colorretal, ovariano e gástrico, hepatocarcinoma, adenocarcinoma pancreático e glioma (GESIERICH et al, 2005;PAN et al, 2015;PARK et al, 2016;VOGLSTAETTER et al, 2019).…”

“…A respeito de nossos resultados, embora não significativos TSPAN8 exibiu uma diminuição do transcrito primário nas amostras tumorais em comparação com tecido normal. Isto evidencia contraste com o trabalho do Voglstaetter e colaboradores que avaliaram a expressão de mRNA de TSPAN8 por RT-qPCR em 15 amostras de câncer mamário sendo 01 tecido normal, 07 tumores primários e 07 metástases de pulmão e linfonodos, relatando uma expressão aumentada nos espécimenes metastáticos, intermediaria em tumores primários e mínima no tecido normal (VOGLSTAETTER et al, 2019). Adicionalmente, isto também foi dissemelhante para câncer colorretal e para de ovário, dado que foram encontrados níveis elevados de transcrito primário e proteína nas amostras tumorais em comparação com os respetivos controles (PARK et al, 2016;ZHANG et al, 2020).…”

“…A interação entre TSPAN8 e β-catenina já foi recentemente relatada como um 'loop' na progressão e invasão no melanoma e em promover a troncicidade no câncer colorretal (EL KHARBILI et al, 2019;ZHAN et al, 2019), entretanto em câncer de mama Tspan8 foi identificado num subconjunto de células-tronco mamárias altamente quiescentes (Lgr5+ Tspan8 hi ), localizado dentro da árvore ductal proximal e cujo transcriptoma se assemelha a carcinoma da mama com baixo nível expressão de claudinas, o que pode refletir em parte o subtipo basal-like (FU et al, 2017). Posteriores estudos demostraram que, em câncer mamário Tspan8 poderia estar atuando na sinalização de E-cadherina/β-catenina acompanhado pelo aumento de vesículas extracelulares circulantes, regulando assim a proliferação e a adesão célula-célula (VOGLSTAETTER et al, 2019).…”