The glycoprotein CD147 defines miRNA‐enriched extracellular vesicles that derive from cancer cells

Abstract

Extracellular vesicles (EVs) are ideal for liquid biopsy, but distinguishing cancer cell‐derived EVs and subpopulations of biomarker‐containing EVs in body fluids has been challenging. Here, we identified that the glycoproteins CD147 and CD98 define subpopulations of EVs that are distinct from classical tetraspanin + EVs in their biogenesis. Notably, we identified that CD147 + EVs have substantially higher microRNA (miRNA) content than tetraspanin + EVs and are selectively enriched in miRNA through the interaction of CD147 with heterogeneous nuclear ribonucleoprotein A2/B1. Studies using mouse xenograft models showed that CD147 + EVs predominantly derive from cancer cells, whereas the majority of tetraspanin + EVs are not of cancer cell origin. Circulating CD147 + EVs, but not tetraspanin + EVs, were significantly increased in prevalence in patients with ovarian and renal cancers as compared to healthy individuals and patients with benign conditions. Furthermore, we found that isolating miRNAs from body fluids by CD147 immunocapture increases the sensitivity of detecting cancer cell‐specific miRNAs, and that circulating miRNAs isolated by CD147 immunocapture more closely reflect the tumor miRNA signature than circulating miRNAs isolated by conventional methods. Collectively, our findings reveal that CD147 defines miRNA‐enriched, cancer cell‐derived EVs, and that CD147 immunocapture could be an effective approach to isolate cancer‐derived miRNAs for liquid biopsy.

Harnessing microRNA-enriched extracellular vesicles for liquid biopsy

“…However, these tetraspanins are ubiquitously expressed ( Maecker et al, 1997 ). A recent study traced the cellular origin of circulating CD9-positive EVs in mice bearing human cervical and renal cancer xenografts and found that the majority (i.e., approximately 70%) of CD9-positive EVs derive from mouse host cells ( Ko et al, 2023 ).…”

“…The glycoprotein CD147 (also known as EMMPRIN or basigin) is one of the most frequently detected proteins in EVs ( Ko et al, 2023 ) and is expressed in at least 25 types of cancers of diverse origin ( Supplementary Table S1 ). CD147 is also expressed in some types of normal cells such as renal tubular epithelial cells, leukocytes, platelets, and endothelial cells ( Kosugi et al, 2015 ).…”

“…CD147 is also expressed in some types of normal cells such as renal tubular epithelial cells, leukocytes, platelets, and endothelial cells ( Kosugi et al, 2015 ). However, it has been shown that renal cancer cells secrete significantly more CD147-positive EVs than normal renal tubular epithelial cells and endothelial cells ( Ko et al, 2023 ). Furthermore, CD147 has been found to be enriched in pancreatic and lung tumor-derived EVs as compared to EVs from normal tissues ( Hoshino et al, 2020 ).…”

MCT4 and CD147 colocalize with MMP14 in invadopodia and support matrix degradation and invasion by breast cancer cells

“…However, the mechanisms proposed to be involved in this have been contentious, including whether the ability of CD147 to regulate MMPs is independent from its role as an MCT chaperone ( Schneiderhan et al, 2009 ). CD147 can reside in the plasma membrane, as well as in subcellular compartments, and can be released from cells in various forms ( Albrechtsen et al, 2019 ; Grass and Toole, 2015 ; Egawa et al, 2006 ; Taylor et al, 2002 ; Ko et al, 2023 ). The relation between CD147 glycosylation state, localization and function is incompletely understood, and both high-glycosylated (HG) and low-glycosylated (LG) forms of CD147 have been suggested to have the capacity for activating MMPs, although the HG form might do so more effectively ( Huang et al, 2013 ; Bai et al, 2014 ).…”

MCT4 and CD147 co-localize with MMP14 in invadopodia and autolysosomes and collectively stimulate breast cancer cell invasion by increasing extracellular matrix degradation

“…However, the mechanisms involved have been contentious, including whether the ability of CD147 to regulate MMPs is independent from its role as an MCT chaperone (Schneiderhan et al, 2009). CD147 can reside in the plasma membrane, in subcellular compartments, and can be released from cells in various forms (Albrechtsen et al, 2019, Grass and Toole, 2015, Egawa et al, 2006, Taylor et al, 2002, Ko et al, 2023. The relation between CD147 glycosylation state, localization and function is incompletely understood, with both high-(HG) and low-glycosylated (LG) CD147 suggested to have the capacity for activating MMPs, although the HG form may do so more effectively (Huang et al, 2013, Bai et al, 2014.…”