Immune Targeting of Tetraspanins Involved in Cell Invasion and Metastasis

Vences-Catalán, Felipe; Levy, Shoshana

doi:10.3389/fimmu.2018.01277

Cited by 41 publications

(32 citation statements)

References 83 publications

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“…Tetraspanins are emerging therapeutic targets for cancers, as multiple family members (e.g., CD81, CD53, CD9, CD151, TSPAN8, and CD37) have been implicated in tumor initiation, promotion, and/or metastasis (de Winde et al, 2017;Vences-Catalán & Levy, 2018;Bonnet et al, 2019;Vences-Catalán et al, 2019). CD81, for example, is expressed in a variety of solid tumors and hematopoietic malignancies, and loss of CD81 inhibits the invasion and metastasis of melanoma, breast, and lung tumor cells (Vences-Catalán et al, 2015).…”

Section: Cd53-assisted B-cell Migrationmentioning

confidence: 99%

Open conformation of tetraspanins shapes interaction partner networks on cell membranes

et al. 2020

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Tetraspanins, including CD53 and CD81, regulate a multitude of cellular processes through organizing an interaction network on cell membranes. Here, we report the crystal structure of CD53 in an open conformation poised for partner interaction. The large extracellular domain (EC2) of CD53 protrudes away from the membrane surface and exposes a variable region, which is identified by hydrogen–deuterium exchange as the common interface for CD53 and CD81 to bind partners. The EC2 orientation in CD53 is supported by an extracellular loop (EC1). At the closed conformation of CD81, however, EC2 disengages from EC1 and rotates toward the membrane, thereby preventing partner interaction. Structural simulation shows that EC1‐EC2 interaction also supports the open conformation of CD81. Disrupting this interaction in CD81 impairs the accurate glycosylation of its CD19 partner, the target for leukemia immunotherapies. Moreover, EC1 mutations in CD53 prevent the chemotaxis of pre‐B cells toward a chemokine that supports B‐cell trafficking and homing within the bone marrow, a major CD53 function identified here. Overall, an open conformation is required for tetraspanin–partner interactions to support myriad cellular processes.

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Section: Cd53-assisted B-cell Migrationmentioning

confidence: 99%

Open conformation of tetraspanins shapes interaction partner networks on cell membranes

et al. 2020

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“…The primary causes of mortality associated with cervical cancer are unsuccessful surgical treatment, tumor recurrence and metastasis ( 10 ). The first step in metastasis is localized invasion, which involves numerous phenotypic changes in the primary tumor ( 11 , 12 ). Malignant epithelial-mesenchymal transition (EMT) is an important factor leading to the development of distant tumor metastases ( 13 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

Knockdown of BRCC3 exerts an anti‑tumor effect on cervical cancer in�vitro

Zhang

Zhou

2018

Mol Med Report

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Cervical cancer is a serious malignancy that affects the health of females. In the present study, the association between breast cancer type 1 susceptibility protein/breast cancer type 2 susceptibility protein-containing complex subunit 3 (BRCC3) and cervical cancer was investigated. Reverse transcription-quantitative polymerase chain reaction and western blotting were performed to determine BRCC3 mRNA and protein expression levels in cervical cancer tissues and cells, in addition to the expression levels of proteins associated with the epithelial-mesenchymal transition (EMT) process in HeLa and SiHa cells. Cell Counting Kit-8, Transwell and wound healing assays were performed to determine the cell viability, invasion and migration abilities of cervical cancer cells, respectively. The results of the present study revealed that BRCC3 expression was significantly increased in cervical cancer tissues, which was also revealed to be associated with the clinical stages and pathological grades of cervical cancer exhibited by patients, in addition to the survival time. Furthermore, BRCC3 expression levels were enhanced in HeLa, SiHa and C-33A cervical cancer cells. BRCC3 interference in HeLa and SiHa cells was revealed to suppress cell viability, invasion and migration abilities via upregulation of E-cadherin expression levels and downregulation of Vimentin, matrix metalloproteinase (MMP)-2, MMP-9, snail family transcriptional repressor (Snai)1 and Snai2 expression levels. In conclusion, the expression levels of BRCC3 were revealed to be increased in cervical cancer tissues, which were positively associated with clinical features of cervical cancer. Furthermore, BRCC3 interference inhibited the cell viability, invasion and migration abilities of HeLa and SiHa cells via regulation of EMT progression and expression levels of Snai family members. In addition, the results of the present study suggested that BRCC3 represents an oncogene associated with cervical cancer, and may also represent a novel therapeutic biomarker for the diagnosis, treatment and prognosis of patients with cervical cancer.

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“…The common theme is the “facilitator” role of tetraspanins [141] and the engagement of TEM in Exo-biogenesis and -binding [142]. Though open questions remain, the poor responsiveness of dbko-MCA suggests a joint blockade of Tspan8 and CD151 efficiently hampering several exosome-provided prerequisites for tumor progression.…”

Section: Resultsmentioning

confidence: 99%

Tspan8 and Tspan8/CD151 knockout mice unravel the contribution of tumor and host exosomes to tumor progression

Zhao

Wang

Hackert

et al. 2018

J Exp Clin Cancer Res

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BackgroundThe tetraspanins Tspan8 and CD151 promote metastasis, exosomes (Exo) being suggested to be important in the crosstalk between tumor and host. The contribution of Tspan8 and CD151 to host versus tumor-derived exosome (TEX) activities being not defined, we approached the questions using 3-methylcholanthrene-induced (MCA) tumors from wt, Tspan8ko, CD151ko and Tspan8/CD151 (db)ko mice, implanted into tetraspanin-competent and deficient hosts.MethodsTumor growth and dissemination, hematopoiesis and angiogenesis were surveyed in wild type (wt), Tspan8ko, CD151ko and dbko mice bearing tetraspanin-competent and -deficient MCA tumors. In vitro studies using tumor cells, bone marrow cells (BMC) and endothelial cells (EC) elaborated the mechanism of serum (s)Exo- and TEX-induced target modulation.ResultsTumors grew in autochthonous and syngeneic hosts differing in Tspan8- and/or CD151-competence. However, Tspan8ko- and/or CD151ko-tumor cell dissemination and settlement in metastatic organs was significantly reduced in the autochthonous host, and less severely in the wt-host. Impaired wt-MCA tumor dissemination in the ko-host confirmed a contribution of host- and tumor-Tspan8/-CD151 to tumor cell dissemination, delivery of sExo and TEX being severely impaired by a Tspan8ko/CD151ko. Coculturing tumor cells, BMC and EC with sExo and TEX revealed minor defects in epithelial mesenchymal transition and apoptosis resistance of ko tumors. Strongly reduced migratory and invasive capacity of Tspan8ko/CD151ko-MCA relies on distorted associations with integrins and CAM and missing Tspan8/CD151-promoted recruitment of proteases. The defects, differing between Tspan8ko- and CD151ko-MCA, were rescued by wt-TEX and, less efficiently Tspan8ko- and CD151ko-TEX. Minor defects in hematopoietic progenitor maturation were based on the missing association of hematopoietic growth factors /− receptors with CD151 and, less pronounced, Tspan8. Rescue of impaired angiogenesis in ko mice by wt-sExo and promotion of angiogenesis by TEX depended on the association of Tspan8 and CD151 with GPCR and RTK in EC and tumor cells.ConclusionsTspan8-/CD151-TEX play central roles in tumor progression. Tspan8-/CD151-sExo and TEX contribute by stimulating angiogenesis. Tspan8 and CD151 fulfill these tasks by associating with function-relevant proteins, the additive impact of Tspan8 and CD151 relying on differences in preferred associations. The distinct Tspan8 and CD151 contributions suggest a blockade of TEX-Tspan8 and -CD151 promising for therapeutic intervention.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0961-6) contains supplementary material, which is available to authorized users.

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Immune Targeting of Tetraspanins Involved in Cell Invasion and Metastasis

Cited by 41 publications

References 83 publications

Open conformation of tetraspanins shapes interaction partner networks on cell membranes

Open conformation of tetraspanins shapes interaction partner networks on cell membranes

Knockdown of BRCC3 exerts an anti‑tumor effect on cervical cancer in�vitro

Tspan8 and Tspan8/CD151 knockout mice unravel the contribution of tumor and host exosomes to tumor progression

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