Tumor markers as an entry for SARS‐CoV‐2 infection?

Cancer patients are at higher risk of infection by a novel strain of coronavirus SARS‐CoV‐2, which causes coronavirus disease COVID‐19. Tumor cells overexpress potential SARS‐CoV‐2 receptors, including the primary viral receptor ACE2. Recent evidence suggests that some tumor markers, including CD147 (basigin), can also provide an entry point for SARS‐CoV‐2 through binding to the viral spike (S) protein. The blockade of CD147 could provide a way of preventing SARS‐CoV‐2 in the absence of specific viral drugs.


Introduction
Coronavirus disease 2019 , the illness caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread across the world, becoming one of the leading causes of death in some places [1,2]. The clinical manifestation of COVID-19 infection includes pneumonia, respiratory illness, gastrointestinal and neurological symptoms, and multiple organ damage [3][4][5][6][7]. In addition to the direct invasion, the immune hyperactivation substantially contributes to the COVID-19 toxicity [7,8]. As the number of COVID-19 infections surpassed 15 million globally and more than 600 000 infected people have died, according to the World Health Organization (WHO) report [9], scientists are struggling to understand the viral tropism better and develop the therapeutic approaches for preventing virus infection.
Cancer patients belong to a high-risk group for SARS-CoV-2 infection, having a more severe course of the disease and a high case fatality rate [10][11][12][13][14]. It can be partially attributed to the older age and the weakened immune system of cancer patients as a consequence of treatment and the immunosuppressive tumor effect [13,14]. However, no conclusive evidence is yet available explaining the susceptibility of the oncology patients to SARS-CoV-2 infection.
Invasion by SARS-CoV-2 and tumor marker expression: causality or coincidence?
The SARS-CoV-2 belongs to b-coronavirus genera and contains a single-stranded, positive-sense RNA genome encoding four structural proteins, including spike (S), nucleocapsid (N), membrane (M) and envelope (E), and several accessory proteins. Coronavirus spike (S) protein mediates the receptor binding of the cell surface and induces the fusion of viral and cellular membranes followed by viral genome entry into human target cells [15]. Analyses of the SARS-CoV-2 genome indicated that the virus uses angiotensin-converting enzyme 2 (ACE2) as the entry receptor [16] that was later confirmed by functional studies of SARS-CoV-2 infection in the hACE2 transgenic mice models [17]. Single-cell RNA sequencing provided evidence that multiple organs with high ACE2 expression, including respiratory tract, lung, esophagus, liver, colon, heart, kidney, ileum, rectum, and stomach, might be vulnerable to SARS-CoV-2 infection [18].
Of note, several types of malignant tumors have high ACE2 expression levels, including colon, kidney, pancreatic, and rectal cancer, which can potentially suggest a higher COVID-19 prevalence for patients with these types of malignancies (Fig. 1A,B). The ACE2 protein was found to be highly expressed in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) [19] that can be associated with a high susceptibility of lung cancer patients to SARS-CoV-2 Infection. On the other hand, cells expressing low ACE2, such as immune cells, can also be potentially infected by SARS-CoV-2 as it was shown for SARS-CoV, suggesting that other receptors may facilitate the virus entry [20,21]. In support of this hypothesis, recent studies showed that another cell surface protein CD147 could potentially bind to SARS-CoV-2 spike protein and serve as an additional infection route [16] (Fig. 1A,C).
Cluster of differentiation 147 (CD147) also termed basigin (BSG), or extracellular matrix metalloproteinase inducer, is a transmembrane glycoprotein with pleiotropic functions that is overexpressed in a broad range of malignant tumors and serves as a promising prognostic biomarker for glioblastoma, colorectal, oral, lung, prostate, and many other types of cancer [22]. CD147 has a substantially higher transcription level in both normal and tumor tissues than ACE2 (Fig. 1B). Furthermore, CD147 plays a role in the inflammatory response as a receptor for cyclophilin A (CyPA), a potent chemotactic factor for inflammatory leukocytes and activator of the intracellular antiviral response [22]. The CD147-interacting partners, such as integrins, which are also abundant in many types of cancer, are additional candidate receptors for SARS-CoV-2 entry. Still, experimental proof for this hypothesis is required [23] (Fig. 1A,B).
Cluster of differentiation 147 represents a promising target for anticancer therapy. Treatment of unresectable hepatocellular carcinoma with 131 I-labeled CD147-specific antibody metuximab (Licartin) combined with transcatheter arterial chemoembolization showed promising safety and efficacy (NCT00829465). The safety and clinical activity of CD147-targeting CAR-T treatment are currently analyzed in phase I clinical trials for patients with recurrent glioblastoma (NCT04045847) and advanced hepatocellular carcinoma (NCT03993743).
A study of Wang et al. posted on BIORxiv showed that CD147 could provide a new entry for SARS-CoV-2 infection. In vitro experiments showed that blocking of CD147 on the surface of African green monkey kidney cells (Vero E6) by meplazumab, a humanized anti-CD147 antibody inhibited SARC-CoV2 replication [16]. According to the preprint report on clinical trial study NCT04275245, meplazumab improved the outcome of patients with COVID-19-associated pneumonia with a favorable safety profile [24]. Of importance, meplazumab does not only target the virus replication but also attenuates T-cell chemotaxis induced by CyPA and therefore inhibits COVID-19-associated inflammation [24].
However, more evidence is warranted to understand the possible correlation between the expression level of CD147 in cells or tissues and SARS-CoV-2 susceptibility. We also need to consider that the most lethal transmission route of SARS-CoV-2 is a lung and bronchial infection. In contrast, the viral concentration in blood is low [25], and the amount of viral particles that reach each organ through the blood is different. Moreover, in addition to the direct invasion, SARS-CoV-2 might damage multiple organs through collateral effects from cytokine overproduction and clotting.
At present, there is no effective treatment method for COVID-19 patients except for a broad-spectrum antiviral medication such as remdesivir (GS-5734) (NCT04365725, NCT04292899). In the absence of specific drugs for SARS-CoV-2, humanized anti-CD147 antibodies such as meplazumab can potentially function as antiviral drugs to block the CD147-spike protein complex formation and prevent the virus from entering the host cell.    [26]. The tentative BSG-SP docking was displayed using the HEX 8.0 program [27,28]. 3D model of BSG and SP interaction was analyzed by HEX 8.0 with fast Fourier transform (FFT) algorithm using the following parameters: Correlation type-Shape + Electro+DRAS; FFT Mode-3D; Post-processing-none; Grid dimension-0.6; Solutions-2000; Receptor range-180; Ligand range-180; Twist range-360; Distance range-40.

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