Receptor of Activated Protein C Promotes Metastasis and Correlates with Clinical Outcome in Lung Adenocarcinoma

Antón, Iker; Molina, Eva; Luis-Ravelo, Diego; Zandueta, Carolina; Valencia, Karmele; Ormazábal, C.; Martínez-Canarias, Susana; Perurena, Naiara; Pajares, María J.; Agorreta, Jackeline; Montuenga, Luis M.; Segura, Víctor; Wistuba, Ignacio I.; Rivas, Javier De Las; Hermida, José; Lecanda, Fernando

doi:10.1164/rccm.201110-1826oc

Cited by 45 publications

(61 citation statements)

References 36 publications

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“…88 Analysis of EPCR expression in lung adenocarcinomas of a large group of patients showed a variable degree of EPCR expression in the lungs of these patients; high EPCR levels appeared to be associated with poor prognosis in stage 1 patients but not in patients with more advanced disease. 74 Heng et al reported significantly higher levels of EPCR expression in lung carcinoma compared with para-carcinoma tissues, and EPCR expression was found to be correlated to tumor size and lymph node metastasis. 85 In breast cancer, EPCR expression was found in in situ carcinoma within the luminal A subtype but not in invasive tumors.…”

Section: Org Frommentioning

confidence: 99%

“…However, EPCR-mediated cell signaling in a tumor cell may promote cancer cell migration, invasion, and angiogenesis and inhibit cancer cell apoptosis. [73][74][75][76] Data from recent studies reflect these opposing effects of EPCR in cancer.…”

Section: Org Frommentioning

confidence: 99%

“…79 In contrast to the above findings, EPCR appears to promote tumor metastasis in lung adenocarcinoma as EPCR silencing or blockade of its interaction with APC reduced infiltration of tumor cells in the target organ and resulted in impaired prometastatic activity. 74 Conversely, EPCR overexpression in lung adenocarcinoma cells increased the metastatic activity in the target organs. 74 It is possible that EPCR on the endothelium of host and EPCR on tumor cells may have opposing effects on cancer metastasis ( Figure 6).…”

Section: Org Frommentioning

confidence: 99%

“…74 Conversely, EPCR overexpression in lung adenocarcinoma cells increased the metastatic activity in the target organs. 74 It is possible that EPCR on the endothelium of host and EPCR on tumor cells may have opposing effects on cancer metastasis ( Figure 6). …”

Section: Org Frommentioning

confidence: 99%

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Endothelial cell protein C receptor: a multiliganded and multifunctional receptor

Rao

Esmon

Pendurthi

2014

Blood

166

109

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Endothelial cell protein C receptor (EPCR) was first identified and isolated as a cellular receptor for protein C on endothelial cells. EPCR plays a crucial role in the protein C anticoagulant pathway by promoting protein C activation. In the last decade, EPCR has received wide attention after it was discovered to play a key role in mediating activated protein C (APC)-induced cytoprotective effects, including antiapoptotic, anti-inflammatory, and barrier stabilization. APC elicits cytoprotective signaling through activation of protease activated receptor-1 (PAR1). Understanding how EPCR-APC induces cytoprotective effects through activation of PAR1, whose activation by thrombin is known to induce a proinflammatory response, has become a major research focus in the field. Recent studies also discovered additional ligands for EPCR, which include factor VIIa, Plasmodium falciparum erythrocyte membrane protein, and a specific variant of the T-cell receptor. These observations open unsuspected new roles for EPCR in hemostasis, malaria pathogenesis, innate immunity, and cancer. Future research on these new discoveries will undoubtedly expand our understanding of the role of EPCR in normal physiology and disease, as well as provide novel insights into mechanisms for EPCR multifunctionality. Comprehensive understanding of EPCR may lead to development of novel therapeutic modalities in treating hemophilia, inflammation, cerebral malaria, and cancer.

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Section: Org Frommentioning

confidence: 99%

Section: Org Frommentioning

confidence: 99%

Section: Org Frommentioning

confidence: 99%

Section: Org Frommentioning

confidence: 99%

See 2 more Smart Citations

Endothelial cell protein C receptor: a multiliganded and multifunctional receptor

Rao

Esmon

Pendurthi

2014

Blood

166

109

View full text Add to dashboard Cite

show abstract

“…The tumor suppressive function of macrophage SR-A was demonstrated in an SR-A null mouse model. Antón and colleagues showed that binding of microenvironment-derived activated protein C to tumor endothelial protein C receptor activated Akt and extracellular signalregulated kinase (ERK), decreased apoptosis, and increased tumor metastatic activity (38). Other research identified microenvironment-related pathways important for lung tumor growth and progression.…”

Section: Tumor Microenvironmentmentioning

confidence: 99%

Update in Lung Cancer and Mesothelioma 2012

Powell

Halmos

Nana‐Sinkam

2013

Am J Respir Crit Care Med

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Lung cancer remains the number one cause of cancer-related death in the United States among both men and women. It is estimated that in 2013, there will be more than 200,000 new diagnoses of lung cancer and nearly 160,000 deaths (1). Despite the discovery and application of targeted therapies, the overall survival (OS) remains poor, with an overall 5-year survival approximating 16%. In addition, there are a growing number of cases among former smokers and never smokers. However, based on research advances in 2012, there is enthusiasm that improvements in early detection, coupled with tobacco cessation and the application of novel genetic and genomics technologies, will lead to improved outcomes. EPIDEMIOLOGYAlthough more than 85% of patients diagnosed with lung cancer will have smoked at some point in their lives, only 15 to 20% of smokers will develop lung cancer, thus suggesting the involvement of additional risk factors. Studies examining the roles of various exposures, including asbestos, welding, arsenic, and concomitant lung diseases, such as chronic obstructive pulmonary disease (COPD), tuberculosis, and pneumonia, as risk factors independent of tobacco consumption are ongoing (2, 3). A recent large epidemiological study in more than 2,000 incident cases of lung cancer cases and control subjects identified a 36% increase in lung cancer risk among welders and flame cutters. Interestingly, welding fumes were an independent risk factor for lung cancer (4). DisparitiesA recent examination of multiple registries confirmed that African Americans have the highest incidence of lung cancer (73/100,000) (5) and have a decreased OS and lower rates of surgical resection. Factors contributing to the disparities in lung cancer include inequities in access to health care, differing perceptions regarding early detection, smoking cessation and treatment, and variation in susceptibilities to the effects of cigarette smoke (6, 7). Conversely, the incidence rates for lung cancer among Hispanic men are much lower, and OS is better than in non-Hispanic whites. The explanations for these differences include a combination of decreased smoking rates among Hispanics, potential genetic variants (8), and histological distribution. Saeed and colleagues conducted a systematic analysis of the SEER database and determined that Hispanics had a higher rate of less aggressive histological subtypes of lung cancer (adenocarcinoma in situ and lepidic predominant adenocarcinoma) (9). Investigation of these areas should help to narrow the lung cancer outcomes gap that exists between ethnic groups.

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Endothelial protein C receptor is overexpressed in colorectal cancer as a result of amplification and hypomethylation of chromosome 20q

Lal

Willcox

Beggs

et al. 2017

The Journal of Pathology CR

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Endothelial Protein C Receptor (EPCR) is a Major Histocompatibility Complex homologue, with established roles downregulating coagulation and in endothelial protection. Expressed predominantly on endothelium, EPCR affects inflammatory, apoptotic and cell proliferation pathways by binding to activated protein C (APC). However, EPCR can also be expressed on cancer cells, although the underlying reasons are unclear. Moreover, although EPCR has been linked with chemosensitivity in lung cancer, its clinical significance in many tumours is unknown. Here, we explored its significance in colorectal cancer (CRC). Bioinformatic methods revealed EPCR overexpression in many epithelial cancers, which was confirmed on CRC epithelial tumour cells by immunohistochemistry. EPCR upregulation resulted from gene amplification and DNA hypomethylation, and occurred in concert with a cohort of neighbouring genes on chromosome 20q, a region previously implicated in chemoresistance. As in endothelial cells, EPCR reproducibly mediated ERK pathway activation in a model CRC cell line following APC treatment. However, EPCR knockdown studies failed to highlight compelling EPCR‐intrinsic impact on CRC cell phenotype, with limited effects on chemosensitivity and no effect on invasion observed, while EPCR appeared to decrease CRC cell migration. Consistent with these observations, differential EPCR expression did not influence response to chemotherapy in a human CRC cohort. Our results provide a compelling explanation for how EPCR is upregulated in diverse epithelial malignancies. They indicate that the clinical significance of EPCR varies across different tumour types. Furthermore, they raise the possibility that the prognostic significance of EPCR in certain tumours relates significantly to co‐upregulation of neighbouring genes on chromosome 20q. Therefore, efforts to exploit EPCR as a prognostic marker should be focussed on specific tumours, and in such scenarios EPCR‐co‐dysregulated genes may represent potential axes for therapeutic intervention.

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Receptor of Activated Protein C Promotes Metastasis and Correlates with Clinical Outcome in Lung Adenocarcinoma

Cited by 45 publications

References 36 publications

Endothelial cell protein C receptor: a multiliganded and multifunctional receptor

Endothelial cell protein C receptor: a multiliganded and multifunctional receptor

Update in Lung Cancer and Mesothelioma 2012

Endothelial protein C receptor is overexpressed in colorectal cancer as a result of amplification and hypomethylation of chromosome 20q

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