Tetraspanin CD9 determines invasiveness and tumorigenicity of human breast cancer cells

Abstract

Interaction of breast cancer cells (BCCs) with stromal components is critical for tumor growth and metastasis. Here, we assessed the role of CD9 in adhesion, migration and invasiveness of BCCs. We used co-cultures of BCCs and bone marrow-derived multipotent mesenchymal stromal cells (MSCs), and analyzed their behavior and morphology by dynamic total internal reflection fluorescence, confocal and scanning electron microscopy. 83, 16 and 10% of contacts between MDA-MB-231 (MDA), MA-11 or MCF-7 cells and MSCs, respectively, resulted in MSC invasion. MDA cells developed long magnupodia, lamellipodia and dorsal microvilli, whereas long microvilli emerged from MA-11 cells. MCF-7 cells displayed large dorsal ruffles. CD9 knockdown and antibody blockage in MDA cells inhibited MSC invasion by 95 and 70%, respectively, suggesting that CD9 is required for this process. Remarkably, CD9-deficient MDA cells displayed significant alteration of their plasma membrane, harboring numerous peripheral and dorsal membrane ruffles instead of intact magnupodium/lamellipodium and microvillus, respectively. Such modification might explain the delayed adhesion, and hence MSC invasion. In agreement with this hypothesis, CD9-knockdown suppressed the metastatic capacity of MDA cells in mouse xenografts. Our data indicate that CD9 is implicated in BCC invasiveness and metastases by cellular mechanisms that involve specific CD9+ plasma membrane protrusions of BCCs.

RBM5 reduces small cell lung cancer growth, increases cisplatin sensitivity and regulates key transformation-associated pathways

“…Other highly downregulated genes common to both T2 and C4 include CD9 , Discs Large Homolog Associated Protein 1 ( DLGAP1 ), and Feline Sarcoma ( FES ). Interestingly, CD9 and FES have previously been associated with cell adhesion and tumor metastasis, with the effect of their expression seeming to be cell type-specific (Delfino et al, 2006; Huan et al, 2015; Kanda et al, 2009; Rappa et al, 2015). Of the two, only CD9 has been investigated in regards to SCLC specifically, and low expression levels were linked to increased motility and invasiveness (Funakoshi et al, 2003).…”

CD9 Tetraspanin: A New Pathway for the Regulation of Inflammation?

“…Regarding pathological models, CD9-knockdown suppresses the invasive and metastatic capacity of breast cancer cells in mouse xenografts ( 45 ), and CD9 deficiency reduces the severity of osteoarthritis in aging and antigen-induced arthritis models ( 46 ); however, CD9 deficiency also induces a phenotype similar to human chronic obstructive pulmonary disease (COPD) ( 47 ). These reports clearly suggest that CD9 is crucial in the control of inflammation and support its role in the modulation of humoral immune responses ( 30 ), the production of myeloid cells ( 10 ) and the secretion of cytokines by macrophages ( 23 ).…”

Transmembrane protein CD9 is glioblastoma biomarker, relevant for maintenance of glioblastoma stem cells

“…Inverse correlation between CD9 expression and tumor cell invasion was shown for ovary cancer, cervical cancer and melanoma [ 17 , 19 ]. When over-expressed, an increased migration and invasion of tumor cells were observed [ 21 ], as well as their reduced apoptosis induction, leading to increased resistance to chemotherapy [ 18 , 22 ]. The mode of CD9 action depends on a number of its binding membrane associated proteins, increasing the variability of affected cellular functions.…”