The versatile roles of testrapanins in cancer from intracellular signaling to cell-cell communication: cell membrane proteins without ligands

Abstract

The tetraspanins (TSPANs) are a family of four-transmembrane proteins with 33 members in mammals. They are variably expressed on the cell surface, various intracellular organelles and vesicles in nearly all cell types. Different from the majority of cell membrane proteins, TSPANs do not have natural ligands. TSPANs typically organize laterally with other membrane proteins to form tetraspanin-enriched microdomains (TEMs) to influence cell adhesion, migration, invasion, survival and induce downstream signaling. Emerging evidence shows that TSPANs can regulate not only cancer cell growth, metastasis, stemness, drug resistance, but also biogenesis of extracellular vesicles (exosomes and migrasomes), and immunomicroenvironment. This review summarizes recent studies that have shown the versatile function of TSPANs in cancer development and progression, or the molecular mechanism of TSPANs. These findings support the potential of TSPANs as novel therapeutic targets against cancer.

Keywords: Cancer; Extracellular vesicles; Immunonology; Metastasis; Tetraspanin.

Fig. 1

The intracellular signaling of TSPANs in cancer. Although mainly located on cell membrane, TSPANs have no natural ligands. They affect different biological processes mainly via interacting with different partner molecules to form TEMs. Integrins are the most prominent partner of TSPANs. Other partners of TSPANs include growth factor receptors (EGFR [9], mtTGF-β [10]), transporters (ASCT2 [11], FATP1 [12], MDR1 [13]), membrane-linked kinases (BTRC [14], SOCSS3 [15], ATXN3 [16]), other transmembrane proteins (ADAM10[17], CD44 [18], p120 [19]). Thus, TSPANs can affect several signaling pathways, including PI3K/AKT, Wnt/β-catenin, ERK1/2, STAT3/5, Src, Notch pathways

Fig. 2

The function of TSPANs in EV biogenesis. TSPANs can regulate the biogenesis of EVs in the following aspects: (1) TEMs are prone for internalization or curvature [106, 107], and proteins in TEMs have been proposed to be carried by EVs [108]; (2) TSPANs contribute to EE traffic towards MVB [109]. (3) The exosome TSPAN web strengthens binding avidity by clustering TSPAN-associated molecules. TSPAN8 could promote EV production and the attachment to target cells. In contrast, TSPAN6 can reduce EV production and the contents in EVs in cancer cells. CD151 facilitates secretion of ribosomal proteins while reducing complement proteins to promote the migration and invasion of triple-negative breast cancer cells [111]. CD81 ensures the membrane integrity of exosomes, which are capable of inducing stemness in triple-negative breast cancer [18]. CD9 on the surface of EVs facilitates the uptake of EVs from cancer-associated fibroblasts by pancreatic cancer cells [117]