Clinical Evolution of Epithelial–Mesenchymal Transition in Human Carcinomas
| Autor: | Li Chen, Rodrigo F. Chuaqui, Sarah B. Miller, Jyothi Subramanian, Larry Rubinstein, Robert J. Kinders, Andrea Regier Voth, Scott M. Lawrence, Apurva K. Srivastava, Tony Navas, Melinda G. Hollingshead, Shivaani Kummar, Hala R. Makhlouf, Katherine V. Ferry-Galow, James H. Doroshow, Ralph E. Parchment, Alice P. Chen, Deborah Wilsker, Mariam M. Konaté, Sergio Y. Alcoser, Suzanne Borgel, Tomas Vilimas, Donald P. Bottaro |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Cancer Research Epithelial-Mesenchymal Transition Indazoles Paclitaxel medicine.medical_treatment Cell Plasticity Vimentin Article Metastasis Targeted therapy Mice 03 medical and health sciences 0302 clinical medicine Antigens CD Cancer stem cell Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols Biomarkers Tumor medicine Carcinoma Animals Humans Epithelial–mesenchymal transition beta Catenin Cell Proliferation Sulfonamides biology Cancer Cadherins medicine.disease Xenograft Model Antitumor Assays Pyrimidines 030104 developmental biology Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer cell Neoplastic Stem Cells Cancer research biology.protein Female Biopsy Large-Core Needle |
| Zdroj: | Cancer Res |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | The significance of the phenotypic plasticity afforded by epithelial–mesenchymal transition (EMT) for cancer progression and drug resistance remains to be fully elucidated in the clinic. We evaluated epithelial–mesenchymal phenotypic characteristics across a range of tumor histologies using a validated, high-resolution digital microscopic immunofluorescence assay (IFA) that incorporates β-catenin detection and cellular morphology to delineate carcinoma cells from stromal fibroblasts and that quantitates the individual and colocalized expression of the epithelial marker E-cadherin (E) and the mesenchymal marker vimentin (V) at subcellular resolution (“EMT-IFA”). We report the discovery of β-catenin+ cancer cells that coexpress E-cadherin and vimentin in core-needle biopsies from patients with various advanced metastatic carcinomas, wherein these cells are transitioning between strongly epithelial and strongly mesenchymal-like phenotypes. Treatment of carcinoma models with anticancer drugs that differ in their mechanism of action (the tyrosine kinase inhibitor pazopanib in MKN45 gastric carcinoma xenografts and the combination of tubulin-targeting agent paclitaxel with the BCR-ABL inhibitor nilotinib in MDA-MB-468 breast cancer xenografts) caused changes in the tumor epithelial–mesenchymal character. Moreover, the appearance of partial EMT or mesenchymal-like carcinoma cells in MDA-MB-468 tumors treated with the paclitaxel–nilotinib combination resulted in upregulation of cancer stem cell (CSC) markers and susceptibility to FAK inhibitor. A metastatic prostate cancer patient treated with the PARP inhibitor talazoparib exhibited similar CSC marker upregulation. Therefore, the phenotypic plasticity conferred on carcinoma cells by EMT allows for rapid adaptation to cytotoxic or molecularly targeted therapy and could create a form of acquired drug resistance that is transient in nature. Significance: Despite the role of EMT in metastasis and drug resistance, no standardized assessment of EMT phenotypic heterogeneity in human carcinomas exists; the EMT-IFA allows for clinical monitoring of tumor adaptation to therapy. |
| Databáze: | OpenAIRE |
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