Positive crosstalk between EGFR and the TF-PAR2 pathway mediates resistance to cisplatin and poor survival in cervical cancer

Almeida, Vitor; Guimarães, Isabella dos Santos; Almendra, Lucas R; Rondon, Araci M. R.; Tilli, Tatiana Martins; Melo, Andréia Cristina de; Sternberg, Cinthya; Monteiro, Robson Q.

doi:10.18632/oncotarget.25748

Cited by 39 publications

(40 citation statements)

References 55 publications

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“…47 More recently, Hugo de Almeide et al showed that TF signaling drives a positive feedback loop in EGFRdependent cisplatin-resistant cervical cancer. 48 That is, the TF:FVIIa signaling complex activates PAR2, which then transactivates EGFR, one of the known regulators of TF and a promotor of chemoresistance. 48 Besides affecting the cell response to chemotherapy negatively, TF is known to sensitize neuroblastoma to doxorubicin.…”

Section: Regulation Of Tissue Factor Transcription and Activitymentioning

confidence: 99%

“…48 That is, the TF:FVIIa signaling complex activates PAR2, which then transactivates EGFR, one of the known regulators of TF and a promotor of chemoresistance. 48 Besides affecting the cell response to chemotherapy negatively, TF is known to sensitize neuroblastoma to doxorubicin. 49 Taken together, chemotherapy-induced cellular responses including induction of apoptosis, induction of cell cycle arrest, and increased PDI localization on the cell surface may all partly explain the procoagulant phenotype observed in chemotherapy-treated cancer patients.…”

Section: Regulation Of Tissue Factor Transcription and Activitymentioning

confidence: 99%

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Role of Tissue Factor in Tumor Progression and Cancer-Associated Thrombosis

Rondon

Kroone

Kapteijn

et al. 2019

Semin Thromb Hemost

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It has been long-established that cancer and thrombosis are linked, but the exact underlying pathological mechanism remains to be unraveled. As the initiator of the coagulation cascade, the transmembrane glycoprotein tissue factor (TF) has been intensely investigated for its role in cancer-associated thrombosis and cancer progression. TF expression is regulated by both specific oncogenes and environmental factors, and it is shown to regulate primary growth and metastasis formation in a variety of cancer models. In clinical studies, TF has been shown to be overexpressed in most cancer types and is strongly associated with disease progression. While TF clearly associates with cancer progression, a prominent role for TF in the development of cancer-associated thrombosis is less clear. The current concept is that cancer-associated thrombosis is associated with the secretion of tumor-derived TF-positive extracellular vesicles in certain tumor types. To date, many therapeutic strategies to target TF—both in preclinical and clinical phase—are being pursued, including targeting TF or the TF:FVIIa complex by itself or by exploiting TF as a docking molecule to deliver cytotoxic compounds to the tumor. In this review, the authors summarize the current understanding of the role of TF in both cancer progression and cancer-associated thrombosis, and discuss novel insights on TF as a therapeutic target as well as a biomarker for cancer progression and VTE.

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Section: Regulation Of Tissue Factor Transcription and Activitymentioning

confidence: 99%

Section: Regulation Of Tissue Factor Transcription and Activitymentioning

confidence: 99%

Role of Tissue Factor in Tumor Progression and Cancer-Associated Thrombosis

Rondon

Kroone

Kapteijn

et al. 2019

Semin Thromb Hemost

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“…Several examples of cancer-related signaling events mediated by coagulation receptors have been characterized and implicated in various aspects of disease pathogenesis, ranging from metastasis and angiogenesis to drug resistance. 15,19,25 It is presently unclear whether, and to what extent, the clinically used pharmacological thromboprophylaxis and anticoagulation measures meaningfully impact cellular events associated with cancer and whether their modification may impact patient survival. 3,26,27 From a mechanistic standpoint, it is reasonable to consider CAT as an aftermath of dysregulated expression and/or function of canonical effector mechanisms within the hemostatic system.…”

mentioning

confidence: 99%

Oncogenes and Clotting Factors: The Emerging Role of Tumor Cell Genome and Epigenome in Cancer-Associated Thrombosis

Tawil

Bassawon

Rak

2019

Semin Thromb Hemost

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There are emerging linkages between biological and genetic aspects of cancer progression and the mechanisms of cancer-associated thrombosis. It is argued that reciprocal influences between cancer cells, their associated vascular stroma, and the hemostatic system may shape the mechanism of coagulopathy. In this regard, glioblastoma multiforme offers a paradigm where the prevalent occurrence of local microthrombosis and peripheral venous thromboembolism can be linked to the profiles of oncogenic driver mutations and their impact on the expression of coagulation-related genes (coagulome). These relationships can be recapitulated in cellular models of glioblastoma, where the expression of tissue factor, podoplanin, and the release of procoagulant microparticles (extracellular vesicles) remains under the control of oncogenic pathways (epidermal growth factor receptor variant III, isocitrate dehydrogenase 1). These pathways define molecular subtypes of glioblastoma that express differential coagulomes. Moreover, single-cell sequencing of glioblastoma samples reveals a combinatorial rather than common profile of both subtype markers and coagulation-related genes. Based on these emerging observations, the authors suggest that cancers may operate as coagulant composites, where individual cells and their dominant populations express different procoagulant phenotypes, resulting in the net impact on the hemostatic system. They suggest that relating these mechanisms to clinical presentations of thrombosis may facilitate a more causality-based, personalized, and possibly cancer-specific thromboprophylaxis and treatment.

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“…Therefore, the use of drugs to suppress PGE 2 synthesis may reduce the risk of cervical lesions. In the treatment of cervical cancer, patients with upregulated expression of COX-2 have a worse prognosis than patients who do not, irrespective of whether radiotherapy or chemotherapy is administered (47,48). Therefore, COX-2 inhibitors, such as ibuprofen and aspirin, may reduce the risk of cervical cancer recurrence (29).…”

Section: Discussionmentioning

confidence: 99%

E6‑regulated overproduction of prostaglandin�E2 may inhibit migration of dendritic cells in human papillomavirus 16‑positive cervical lesions

et al. 2020

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Continuous human papillomavirus (HPV) infection is a critical cause of cervical lesions; however, the specific mechanism is currently not clear. E6 is one of the most important oncoproteins associated with HPV, which regulates synthases in the production of prostaglandin E2 (PGE 2 ). Notably, PGE 2 has been reported to be upregulated in cervical lesions. An insufficient number of mature dendritic cells (DCs), which is unable to cause an effective immune response, is an important cause of cervical lesions. Therefore, this study explored the possible causes of HPV16-positive cervical lesions by identifying the relationship between E6, PGE 2 and DCs. Firstly, the distribution and status of DCs in clinical biopsy specimens and animal models were analyzed with immunohistochemistry and flow cytometry, which demonstrated that the migratory ability of DCs was inhibited in HPV16-positive cervical lesions. Furthermore, using immunohistochemistry, western blotting and ELISA, it was revealed that as the degree of cervical lesions increased, the expression of PGE 2 and its synthases increased. Subsequently, as determined using Transwell and 3D migration assays, it was revealed that a high concentration of PGE 2 inhibited the migration of DCs, which may explain the phenomenon observed in cervical lesions. Notably, E6 was identified to regulate PGE 2 expression. The in vivo experiments indicated that E6 may increase the expression levels of PGE 2 in cervical lesions, which could eventually induce inhibition of the migration of DCs. In conclusion, the present study suggested that E6 regulated overproduction of PGE 2 , which may induce inhibition of DC migration in HPV16-positive cervical lesions.

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Positive crosstalk between EGFR and the TF-PAR2 pathway mediates resistance to cisplatin and poor survival in cervical cancer

Cited by 39 publications

References 55 publications

Role of Tissue Factor in Tumor Progression and Cancer-Associated Thrombosis

Role of Tissue Factor in Tumor Progression and Cancer-Associated Thrombosis

Oncogenes and Clotting Factors: The Emerging Role of Tumor Cell Genome and Epigenome in Cancer-Associated Thrombosis

E6‑regulated overproduction of prostaglandin�E2 may inhibit migration of dendritic cells in human papillomavirus 16‑positive cervical lesions

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