Disrupting VEGF-A paracrine and autocrine loops by targeting SHP-1 suppresses triple negative breast cancer metastasis
| Autor: | Hao-Chieh Chiu, Pei-Yi Chu, Te-Chang Lee, Jung Chen Su, Chung Wai Shiau, Ling Ming Tseng, Kuen-Feng Chen, Chia Yun Wu, Wei Tien Tai, Szu Hsien Wu, Chunyu Liu, Ai-Chung Mar |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
STAT3 Transcription Factor
Vascular Endothelial Growth Factor A 0301 basic medicine medicine.medical_specialty Pyridines Mice Nude Triple Negative Breast Neoplasms Kaplan-Meier Estimate medicine.disease_cause Article Metastasis 03 medical and health sciences Paracrine signalling chemistry.chemical_compound 0302 clinical medicine Cell Movement Cell Line Tumor Internal medicine Regorafenib Paracrine Communication medicine Animals Humans Neoplasm Metastasis Autocrine signalling Triple-negative breast cancer Multidisciplinary biology Phenylurea Compounds Protein Tyrosine Phosphatase Non-Receptor Type 6 medicine.disease Xenograft Model Antitumor Assays Autocrine Communication 030104 developmental biology Endocrinology chemistry 030220 oncology & carcinogenesis biology.protein Cancer research Female Carcinogenesis Tyrosine kinase Platelet-derived growth factor receptor |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep28888 |
| Popis: | Patients with triple-negative breast cancer (TNBC) had an increased likelihood of distant recurrence and death, as compared with those with non-TNBC subtype. Regorafenib is a multi-receptor tyrosine kinase (RTK) inhibitor targeting oncogenesis and has been approved for metastatic colorectal cancer and advanced gastrointestinal stromal tumor. Recent studies suggest regorafenib acts as a SHP-1 phosphatase agonist. Here, we investigated the potential of regorafenib to suppress metastasis of TNBC cells through targeting SHP-1/p-STAT3/VEGF-A axis. We found a significant correlation between cancer cell migration and SHP-1/p-STAT3/VEGF-A expression in human TNBC cells. Clinically, high VEGF-A expression is associated with worse disease-free and distant metastasis-free survival. Regorafenib induced significant anti-migratory effects, in association with downregulation of p-STAT3 and VEGF-A. To exclude the role of RTK inhibition in regorafenib-induced anti-metastasis, we synthesized a regorafenib derivative, SC-78, that had minimal effect on VEGFR2 and PDGFR kinase inhibition, while having more potent effects on SHP-1 activation. SC-78 demonstrated superior in vitro and in vivo anti-migration to regorafenib. Furthermore, VEGF-A dependent autocrine/paracrine loops were disrupted by regorafenib and SC-78. This study implies that SHP-1/p-STAT3/VEGF-A axis is a potential therapeutic target for metastatic TNBC and the more potent SC-78 may be a promising lead for suppressing metastasis of TNBC. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|