ANTXR1 (TEM8) overexpression in gastric adenocarcinoma makes the protein a potential target of immunotherapy

Sotoudeh, Masoud; Shakeri, Ramin; Dawsey, Sanford M.; Sharififard, Bahareh; Ahmadbeigi, Naser; Naderi, Mahmood

doi:10.1007/s00262-019-02392-y

Cited by 9 publications

(15 citation statements)

References 19 publications

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“…In the current study, we found that ANTXR1 was not only aberrantly upregulated in GC tissues but also significantly correlated with depth of tumor invasion and disease stage, Lauren classification, histological grade, tumor size, and race, indicating that tumors with high expression of ANTXR1 are malignant and aggressive. Consistent with a previous study (Sotoudeh et al, 2019), our research also revealed that ANTXR1 is an independent prognostic indicator for GC patients and overexpression of ANTXR1 was significantly associated with poor clinical outcomes. Taken together, ANTXR1 is an outstanding candidate for prognostic biomarker and therapeutic target of GC patients.…”

Section: Discussionsupporting

confidence: 92%

“…Moreover, Byrd TT and colleagues developed anti-ANTXR1 chimeric antigen receptor T cell for targeted therapy of triple-negative breast cancer and successfully induced regression of established patient-derived xenograft tumors (Byrd et al, 2018). Recently, Sotoudeh et al reported that ANTXR1 was overexpressed in GC and a promising molecular target for both clinical and preclinical assessment for immunotherapy of stomach cancer (Sotoudeh et al, 2019). The above findings implicate that ANTXR1 plays a vital role in tumor angiogenesis, progression, invasion and metastasis, thus making it a potential immunotherapeutic target.…”

Section: Introductionmentioning

confidence: 99%

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ANTXR1 Is a Prognostic Biomarker and Correlates With Stromal and Immune Cell Infiltration in Gastric Cancer

Huang

Zhang

Zheng

2020

Front. Mol. Biosci.

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Gastric cancer (GC) is a complex and heterogeneous disease, making it difficult to ascertain the optimal therapeutic approach for individual GC patients. Stromal and immune cell infiltration in GC has a strong correlation with clinical outcomes; however, the underlying mechanisms that drive immunosuppression remain vastly undiscovered. Recent studies validated that anthrax toxin receptor 1 (ANTXR1) is aberrantly expressed in several cancers and holds promise as a new therapeutic target for cancer. However, its immunological roles in GC are still unclear. Here, we show that we identify the distinct stromal and immune cell infiltration in GC between the high and low ANTXR1 expression group by analyzing genomic data. Clinically, ANTXR1 is highly expressed in GC and correlates with adverse clinicopathological characteristics. Additionally, high ANTXR1 expression is linked to markedly poor clinical outcomes and resistance to chemotherapy, whereas the low ANTXR1 expression group is correlated with better outcomes and response to chemotherapy in GC patients. We further revealed the differential landscape of somatic tumor mutation burden (TMB) between the two groups and observed that patients with high ANTXR1 expression suffered from a lower TMB, potentially leading to less sensitivity to checkpoint therapy. Molecularly, results displayed that ANTXR1 is an immunosuppressive element, which may perform its function via promoting the secretion of immunosuppressive factors that play a significant role in modulating tumor-associated fibroblast transformation, M2 macrophage polarization, and T cell exhaustion. Gene set enrichment analysis revealed that cancer-related pathways including epithelial-to-mesenchymal transition, focal adhesion, and transforming growth factor-β (TGF-β) signaling pathways were enriched in high ANTXR1 expression tumors. Our work suggests that ANTXR1 could not only serve as a valuable prognostic biomarker in GC but also be deemed as a potential immunotherapeutic target and useful biomarker of sensitivity to chemotherapy.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

ANTXR1 Is a Prognostic Biomarker and Correlates With Stromal and Immune Cell Infiltration in Gastric Cancer

Huang

Zhang

Zheng

2020

Front. Mol. Biosci.

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“…Recent studies have revealed that antibodies targeting ANTXR1 exert unique antitumor effects by selectively inhibiting stromal endothelial cells (Liu et al, 2016). In addition, ANTXR1 is regarded as a potential target for CAR T cell immunotherapies in gastric adenocarcinoma (Sotoudeh et al, 2019), which makes it more applicable for clinical treatment. Using integrated bioinformatic and machine learning algorithms, we elucidated the genomic landscape of GC and its correlation with TMB, the stromal compartment, and immune cell infiltration.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Gastric Cancer Tumor Microenvironment Characterization Reveals Stromal-Related Gene Signatures Associated With Macrophage Infiltration

Wei

Lou

et al. 2020

Front. Genet.

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The tumor microenvironment (TME) has attracted attention owing to its essential role in tumor initiation, progression, and metastasis. With the emergence of immunotherapies for various cancers, and their high efficacy, an understanding of the TME in gastric cancer (GC) is critical. The aim of this study was to investigate the effect of various components within the GC TME, and to identify mechanisms that exhibit potential as therapeutic targets. The ESTIMATE algorithm was used to quantify immune and stromal components in GC samples, whose clinicopathological significance and relationship with predicted outcomes were explored. Low tumor mutational burden and high M2 macrophage infiltration, which are considered immune suppressive characteristics and may be responsible for unfavorable prognoses in GC, were observed in the high stromal group (HR = 1.585; 95% CI, 1.112-2.259; P = 0.009). Furthermore, weighted correlation network, differential expression, and univariate Cox analyses were used, along with machine learning methods (LASSO and SVM-RFE), to reveal genome-wide immune phenotypic correlations. Eight stromal-relevant genes cluster (FSTL1, RAB31, FBN1, ANTXR1, LRRC32, CTSK, COL5A2, and ENG) were identified as adverse prognostic factors in GC. Finally, using a combination of TIMER database and single-sample gene set enrichment analyses, we found that the identified genes potentially contribute to macrophage recruitment and polarization of tumor-associated macrophages. These findings provide a different perspective into the immune microenvironment and indicate potential prognostic and therapeutic targets for GC immunotherapies.

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“…Early studies[ 11 ] have found that high expression of ANTXR1 can be detected in paracancerous tissues of a variety of malignant tumors, suggesting that ANTXR1 is involved in regulating tumor growth and metastasis. Evans et al [ 12 ] in 2018 found that Seneca Valley virus (SVV) uses ANTXR1 to enter cells, which is the same as the surface receptors pirated by anthrax toxins from bacteria.…”

Section: Antxr1 Regulates Tumor Growth and Metastasismentioning

confidence: 99%

Latest therapeutic target for gastric cancer: Anthrax toxin receptor 1

Sun¹,

Lv²,

Chen³

et al. 2021

WJGO

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Anthrax toxin receptor 1 (ANTXR1), also known as tumor endothelial marker 8, is a highly conserved cell surface protein overexpressed in tumor-infiltrating vessels. It was first found in vascular endothelial cells of human colorectal cancer. Although our understanding of its physiological function is limited, it has been found that ANTXR1 binds collagen and promotes migration of endothelial cells in vitro . ANTXR1 is upregulated in vessels of different tumor types in mice and humans, and is also expressed by tumor cells themselves in some tumors, such as gastric, lung, intestinal and breast cancer. Developmental angiogenesis and wound healing were not disturbed in ANTXR1 knockout mice, but compared with wild-type mice, growth of melanoma was impaired after ANTXR1 knockout, indicating that host-derived ANTXR1 can promote tumor growth on the basis of immune activity. Previous studies have shown that ANTXR1 vaccines or sublethal doses of anthrax toxin can inhibit angiogenesis, slow tumor growth and prolong survival. These studies suggest that ANTXR1 is necessary for tumor rather than physiological angiogenesis. It has been found that ANTXR1 plays an important role in tumor angiogenesisas well as in the growth and metastasis of many kinds of tumors. This article reviews the physiological function of ANTXR1 and its role in different kinds of cancer.

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ANTXR1 (TEM8) overexpression in gastric adenocarcinoma makes the protein a potential target of immunotherapy

Cited by 9 publications

References 19 publications

ANTXR1 Is a Prognostic Biomarker and Correlates With Stromal and Immune Cell Infiltration in Gastric Cancer

ANTXR1 Is a Prognostic Biomarker and Correlates With Stromal and Immune Cell Infiltration in Gastric Cancer

Gastric Cancer Tumor Microenvironment Characterization Reveals Stromal-Related Gene Signatures Associated With Macrophage Infiltration

Latest therapeutic target for gastric cancer: Anthrax toxin receptor 1

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