Role of Platelet C-Type Lectin-Like Receptor 2 in Promoting Lung Metastasis in Osteosarcoma

Ichikawa, Junichiro; Ando, Takashi; Kawasaki, Tomonori; Sasaki, Takeshi; Shirai, Toshiaki; Tsukiji, Nagaharu; Kimura, Yujiro; Aoki, Katsumi; Hayakawa, Keiko; Suzuki‐Inoue, Katsue; Saitoh, Masao; Haro, Hirotaka

doi:10.1002/jbmr.4045

Cited by 19 publications

(9 citation statements)

References 37 publications

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“…Consequently, the proliferation of gastric cancer cell lines was suppressed ( Xu L. et al, 2020 ). Besides, CLEC2 promoted lung metastasis of osteosarcoma carcinoma through cell adhesion through interaction with podoplanin ( Schlesinger, 2018 ; Ichikawa et al, 2020 ). In summary, CLECs are crucial in activating the immune response, despite that the mechanisms underlying the association of CLECs with the development of HCC through reshaping immune system is unclear.…”

Section: Introductionmentioning

confidence: 99%

CLEC4s as Potential Therapeutic Targets in Hepatocellular Carcinoma Microenvironment

Zhang

Wei

Fan

et al. 2021

Front. Cell Dev. Biol.

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Immunosuppressive tumor microenvironment in hepatocellular carcinoma (HCC) is critical in tumor development. C-type (Ca2+ -dependent) lectin (CLEC) receptors, essential in innate pattern recognition, have potential regulatory effects on immune cell trafficking and modulatory effects on cancer cell activity. However, information on the expression and prognostic value of CLECs in HCC is scanty. Herein, we explored the potential role of CLECs in HCC based on TCGA, ONCOMINE, GEPIA, UALCAN, cBioPortal, Metascape, TRRUST, and TIMER databases. Results demonstrated a significantly higher mRNA level of CLEC4A and CLEC4L in HCC tissues than normal liver tissues. Contrarily, we found significantly low CLEC4G/H1/H2/M expression in HCC tissues. The IHC analysis revealed the following: Absence of CLEC4A/J/K/M in normal and liver cancer tissues; high CLEC4C expression in HCC tissues; low expression and zero detection of CLEC4D/E/H1/H2/L in HCC tissues and normal tissues, respectively. And the HepG2 and LX-2 were used to verify the expression level of CLEC4s via qRT-PCR in vitro. Furthermore, the expression of CLEC4H1 (ASGR1) and CLEC4H2 (ASGR2) exhibited a significant relation to clinical stages. However, the expression of CLEC4A, CLEC4D, CLEC4E, CLEC4J (FCER2), CLEC4K (CD207), CLEC4G, CLEC4H1, CLEC4M, and CLEC4H2 decreased with tumor progression. Patients expressing higher CLEC4H1/H2 levels had longer overall survival than patients exhibiting lower expression. Moreover, CLEC4A/D/E/J/K/G/H1/M/H2 had significant down-regulated levels of promoter methylation. The expression level of CLEC4s was correlated with the infiltration of B cells, CD8 + T cells, CD4 + T cells, macrophage cells, neutrophil cells, and dendritic cells. Functional analysis revealed the potential role of CLECL4s in virus infection, including COVID-19. Also, hsa-miR-4278 and hsa-miR-324-5p, two potential miRNA targets of CLEC4s, were uncovered. This article demonstrates that CLEC4 is crucial for the development of HCC and is associated with infiltration of various immune cells, providing evidence for new immunotherapy targets in HCC.

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Section: Introductionmentioning

confidence: 99%

CLEC4s as Potential Therapeutic Targets in Hepatocellular Carcinoma Microenvironment

Zhang

Wei

Fan

et al. 2021

Front. Cell Dev. Biol.

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“…As a poor prognostic indicator, thrombocytosis is associated with lymph node metastasis and invasion in cancer patients ( 24 , 67 ). In consistent, platelet transfusion significantly enhanced metastasis of cancer cells in the murine experimental models ( 15 , 68 ). However, platelet decoys bound to tumor cells as effectively as normal intact platelets and inhibited thrombosis and metastatic tumor formation, further supporting the role of platelets in metastasis ( 69 ).…”

Section: Roles Of Platelets In Cancermentioning

confidence: 75%

“…Moreover, anti-PDPN antibody SZ-168 reduced the incidence of VTE in mice ( 194 ). Similar to PDPN mAbs, anti-CLEC2 antibody 2A2B10 suppressed intratumoral thrombus formation as well as metastasis in mice ( 68 , 127 ). These investigations suggest that mAbs neutralizing either CLEC2 or PDPN specifically inhibit platelet-tumor interaction and tumor metastasis.…”

Section: Targeting Platelet-tumor Interaction For Chemotherapymentioning

confidence: 98%

“…Treatment with a CLEC2 inhibitor Co-HP suppressed lung metastasis of PDPN-expressing melanoma cells, but not that of PDPN-negative lung cancer cells ( 126 ). In platelet-depleted mice, platelet transfusion induced much more lung colonization as well as bone metastasis of PDPN-expressing osteosarcoma cells, while CLEC2 mAb injection reduced lung colonization ( 68 ). Likewise, injection of PDPN mAb (MS-1) remarkably suppressed platelet aggregation as well as lung metastasis in the murine cancer metastasis model ( 128 ).…”

Section: Interaction Between Platelets and Cancer: Clec2-pdpn-erm Axismentioning

confidence: 99%

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Platelet CLEC2-Podoplanin Axis as a Promising Target for Oral Cancer Treatment

et al. 2021

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Cancer tissues are not just simple masses of malignant cells, but rather complex and heterogeneous collections of cellular and even non-cellular components, such as endothelial cells, stromal cells, immune cells, and collagens, referred to as tumor microenvironment (TME). These multiple players in the TME develop dynamic interactions with each other, which determines the characteristics of the tumor. Platelets are the smallest cells in the bloodstream and primarily regulate blood coagulation and hemostasis. Notably, cancer patients often show thrombocytosis, a status of an increased platelet number in the bloodstream, as well as the platelet infiltration into the tumor stroma, which contributes to cancer promotion and progression. Thus, platelets function as one of the important stromal components in the TME, emerging as a promising chemotherapeutic target. However, the use of traditional antiplatelet agents, such as aspirin, has limitations mainly due to increased bleeding complications. This requires to implement new strategies to target platelets for anti-cancer effects. In oral squamous cell carcinoma (OSCC) patients, both high platelet counts and low tumor-stromal ratio (high stroma) are strongly correlated with increased metastasis and poor prognosis. OSCC tends to invade adjacent tissues and bones and spread to the lymph nodes for distant metastasis, which is a huge hurdle for OSCC treatment in spite of relatively easy access for visual examination of precancerous lesions in the oral cavity. Therefore, locoregional control of the primary tumor is crucial for OSCC treatment. Similar to thrombocytosis, higher expression of podoplanin (PDPN) has been suggested as a predictive marker for higher frequency of lymph node metastasis of OSCC. Cumulative evidence supports that platelets can directly interact with PDPN-expressing cancer cells via C-type lectin-like receptor 2 (CLEC2), contributing to cancer cell invasion and metastasis. Thus, the platelet CLEC2-PDPN axis could be a pinpoint target to inhibit interaction between platelets and OSCC, avoiding undesirable side effects. Here, we will review the role of platelets in cancer, particularly focusing on CLEC2-PDPN interaction, and will assess their potentials as therapeutic targets for OSCC treatment.

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“…C-type lectin domain family 1 member B (CLEC1B), a tumor platelet-related molecule secreted by activated platelets in the peri-tumor area, could affect thrombus formation and hematogenous metastasis of tumors through interactions with podoplanin [ 39 ]. Blocking the interaction might be a promising therapeutic strategy for preventing pulmonary metastases from osteosarcoma [ 40 ]. Cordycepin treatment effectively reduced the proliferation and migration ability of gastric cancer cells by upregulating CLEC1B [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

A novel tumor doubling time-related immune gene signature for prognosis prediction in hepatocellular carcinoma

Zhang

et al. 2021

Cancer Cell Int

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Background Hepatocellular carcinoma (HCC) has become a global health issue of wide concern due to its high prevalence and poor therapeutic efficacy. Both tumor doubling time (TDT) and immune status are closely related to the prognosis of HCC patients. However, the association between TDT-related genes (TDTRGs) and immune-related genes (IRGs) and the value of their combination in predicting the prognosis of HCC patients remains unclear. The current study aimed to discover reliable biomarkers for anticipating the future prognosis of HCC patients based on the relationship between TDTRGs and IRGs. Methods Tumor doubling time-related genes (TDTRGs) were acquired from GSE54236 by using Pearson correlation test and immune-related genes (IRGs) were available from ImmPort. Prognostic TDTRGs and IRGs in TCGA-LIHC dataset were determined to create a prognostic model by the LASSO-Cox regression and stepwise Cox regression analysis. International Cancer Genome Consortium (ICGC) and another cohort of individual clinical samples acted as external validations. Additionally, significant impacts of the signature on HCC immune microenvironment and reaction to immune checkpoint inhibitors were observed. Results Among the 68 overlapping genes identified as TDTRG and IRG, a total of 29 genes had significant prognostic relevance and were further selected by performing a LASSO-Cox regression model based on the minimum value of λ. Subsequently, a prognostic three-gene signature including HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1), C-type lectin domain family 1 member B (CLEC1B), and Collectin sub-family member 12 (COLEC12) was finally identified by stepwise Cox proportional modeling. The signature exhibited superior accuracy in forecasting the survival outcomes of HCC patients in TCGA, ICGC and the independent clinical cohorts. Patients in high-risk subgroup had significantly increased levels of immune checkpoint molecules including PD-L1, CD276, CTLA4, CXCR4, IL1A, PD-L2, TGFB1, OX40 and CD137, and are therefore more sensitive to immune checkpoint inhibitors (ICIs) treatment. Finally, we first found that overexpression of CLEC1B inhibited the proliferation and migration ability of HuH7 cells. Conclusions In summary, the prognostic signature based on TDTRGs and IRGs could effectively help clinicians classify HCC patients for prognosis prediction and individualized immunotherapies.

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Role of Platelet C-Type Lectin-Like Receptor 2 in Promoting Lung Metastasis in Osteosarcoma

Cited by 19 publications

References 37 publications

CLEC4s as Potential Therapeutic Targets in Hepatocellular Carcinoma Microenvironment

CLEC4s as Potential Therapeutic Targets in Hepatocellular Carcinoma Microenvironment

Platelet CLEC2-Podoplanin Axis as a Promising Target for Oral Cancer Treatment

A novel tumor doubling time-related immune gene signature for prognosis prediction in hepatocellular carcinoma

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