The Context-Dependent Impact of Integrin-Associated CD151 and Other Tetraspanins on Cancer Development and Progression: A Class of Versatile Mediators of Cellular Function and Signaling, Tumorigenesis and Metastasis

SIMPLE SUMMARY: Tetraspanins are a family of molecules abundantly expressed on the surface of normal or tumor cells. They have been implicated in recruiting or sequestering key molecular regulators of malignancy of a variety of human cancers, including breast and lung cancers, glioblastoma and leukemia. Yet, how their actions take place remains mysterious due to a lack of traditional platform for molecular interactions. The current review digs into this mystery by examining findings from recent studies of multiple tetraspanins, particularly CD151. The molecular basis for differential impact of tetraspanins on tumor development, progression, and spreading to secondary sites is highlighted, and the complexity and plasticity of their control over tumor cell activities and interaction with their surroundings is discussed. Finally, an outlook is provided regarding tetraspanins as candidate biomarkers and targets for the diagnosis and treatment of human cancer. ABSTRACT: As a family of integral membrane proteins, tetraspanins have been functionally linked to a wide spectrum of human cancers, ranging from breast, colon, lung, ovarian, prostate, and skin carcinomas to glioblastoma. CD151 is one such prominent member of the tetraspanin family recently suggested to mediate tumor development, growth, and progression in oncogenic context- and cell lineage-dependent manners. In the current review, we summarize recent advances in mechanistic understanding of the function and signaling of integrin-associated CD151 and other tetraspanins in multiple cancer types. We also highlight emerging genetic and epigenetic evidence on the intrinsic links between tetraspanins, the epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), and the Wnt/β-catenin pathway, as well as the dynamics of exosome and cellular metabolism. Finally, we discuss the implications of the highly plastic nature and epigenetic susceptibility of CD151 expression, function, and signaling for clinical diagnosis and therapeutic intervention for human cancer.