4.6 Review

Prognostic value and multifaceted roles of tetraspanin CD9 in cancer

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A peptide binding to the tetraspanin CD9 reduces cancer metastasis

Thanawat Suwatthanarak et al.

Summary: As an organizer of multi-molecular membrane complexes, CD9 is involved in cancer metastasis and serves as a potential therapeutic target. This study evaluated the suppressive effects of CD9-binding peptide (CD9-BP) on cancer cell metastasis and investigated its mechanisms of action. CD9-BP impaired CD9-related functions by disrupting the formation of tetraspanin webs-networks composed of CD9 and its partner proteins. In vitro experiments demonstrated that CD9-BP inhibited cancer cell migration, invasion, exosome secretion, and uptake, critical processes in metastasis. Additionally, in a mouse model, CD9-BP significantly reduced lung metastasis. These findings provide insights into the inhibitory mechanism of CD9-BP on CD9-dependent functions and highlight its potential as a therapeutic nano-biomaterial for metastatic cancers.

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Tetraspanin CD9 Expression Predicts Sentinel Node Status in Patients with Cutaneous Melanoma

Guendalina Lucarini et al.

Summary: The expression of CD9 in melanocytic nevi and cutaneous melanomas is correlated with invasiveness and metastatic potential, and it could be a valid prognostic factor for lymph node metastasis risk.

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Neoadjuvant chemotherapy endows CD9 with prognostic value that differs between tumor and stromal areas in patients with pancreatic cancer

Xuan Han et al.

Summary: The expression of CD9 in pancreatic cancer patients is significantly correlated with clinical and pathological features. In the neoadjuvant group, high levels of tumor CD9 expression are associated with poorer survival, while high levels of stromal CD9 expression are associated with better survival. CD9 has an independent prognostic impact in pancreatic cancer patients.

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CD9 mediates the uptake of extracellular vesicles from cancer-associated fibroblasts that promote pancreatic cancer cell aggressiveness

Jeremy Nigri et al.

Summary: In pancreatic ductal adenocarcinoma (PDAC), signaling from stromal cells through extracellular vesicles (EVs) is involved in metastatic progression. This study identified CD9 as a key component of EVs derived from cancer-associated stromal fibroblasts (CAFs), which mediate the cross-talk between tumor cells and the stroma. Blocking CD9 impaired the uptake of EVs into PDAC cells, and CD9(+) EVs induced MAPK pathway activation, cell migration, and EMT. Inhibiting CD9 or p38 MAPK signaling impaired EV-induced cell migration and EMT. Bioinformatic analysis showed that CD9 abundance is an independent prognostic marker for poor prognosis in PDAC patients.

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Anti-Human CD9 Fab Fragment Antibody Blocks the Extracellular Vesicle-Mediated Increase in Malignancy of Colon Cancer Cells

Mark F. Santos et al.

Summary: Intercellular communication between cancer cells and healthy cells in the tumor microenvironment plays a crucial role in cancer progression and metastasis. Extracellular vesicles (EVs) have emerged as novel mediators in this communication. In this study, the researchers developed a monovalent Fab fragment antibody targeting CD9 tetraspanin and demonstrated its effectiveness in blocking the internalization of melanoma cell-derived EVs and the transfer of their cargo proteins. The study also showed the potential of this anti-CD9 Fab antibody in inhibiting the phenotypic transformation and migration of colorectal cancer cells. Intercepting EV-mediated communication in the tumor niche with this antibody could lead to new anti-cancer therapeutic strategies.
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Transmembrane proteins tetraspanin 4 and CD9 sense membrane curvature

Raviv Dharan et al.

Summary: This study uncovers the mechanisms by which tetraspanin4 and CD9, two tetraspanin proteins, prefer positive membrane curvature and play important roles in migrasome formation and oocyte microvilli shaping. These findings shed light on the membrane remodeling processes and provide insights into the functions of tetraspanin proteins.

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CD9, a tetraspanin target for cancer therapy?

Aurelio Lorico et al.

Summary: In this review, the history of CD9 involvement in oncogenesis and cancer metastasis is briefly discussed, highlighting its potential value as a tumor-associated antigenic target. CD9 has been identified as a favorable prognostic marker or predictor of metastatic potential depending on the cancer type. Besides its use as an antigenic biomarker, CD9 plays a role in intercellular communication under physiological and pathological conditions, notably in the establishment of cancer metastases.

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Mechanistic and Therapeutic Implications of Extracellular Vesicles as a Potential Link Between Covid-19 and Cardiovascular Disease Manifestations

Gianluigi Pironti et al.

Summary: Extracellular vesicles (EVs) are double-layered membrane particles found in circulating body fluids, serving as a tool for intercellular communication and influencing physiological and pathological conditions. Viruses can utilize EVs to exit and enter cells, suggesting a shared cell entry and biogenesis mechanism with EVs. EVs may play a role in the spread of viruses like SARS-CoV-2 and could be linked to cardiovascular manifestations of diseases like Covid-19.

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Prognostic Value of CD9 in Solid Tumor: A Systematic Review and Meta-Analysis

Ping Zeng et al.

Summary: This meta-analysis revealed a strong association between decreased CD9 expression and poor prognosis in solid tumors, particularly in lung cancer and head and neck cancer patients. CD9 may serve as a valuable prognostic predictive biomarker and potential therapeutic target in human solid tumors.

FRONTIERS IN ONCOLOGY (2021)

Article Cell Biology

CD9 inhibition reveals a functional connection of extracellular vesicle secretion with mitophagy in melanoma cells

Henar Suarez et al.

Summary: Tetraspanin CD9 plays a role in regulating early endosome numbers and is functionally connected with mitophagy, mitochondrial quality control, and cell proliferation. CD9 peptide and gene deletion result in different effects on cellular processes, with CD9 KO cells compensating for mitochondrial dysfunction by increasing total mitochondrial mass.

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Increased CD9 expression predicts favorable prognosis in human cancers: a systematic review and meta-analysis

Hyun Min Koh et al.

Summary: The meta-analysis showed that increased CD9 expression is associated with more favorable survival in cancer patients, especially in breast cancer and head and neck cancer.

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Structural insights into tetraspanin CD9 function

Rie Umeda et al.

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Liang Dong et al.

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Expression of CD9 and CD82 in papillary thyroid microcarcinoma and its prognostic significance

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Tetraspanin blockage reduces exosome-mediated HIV-1 entry

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

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Deletion of Tetraspanin CD9 Diminishes Lymphangiogenesis in Vivo and in Vitro

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