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Targeting Pancreatic Cancer Cell Plasticity: The Latest in Therapeutics

Mortality remains alarmingly high for patients diagnosed with pancreatic ductal adenocarcinoma (PDAC), with 93% succumbing to the disease within five years. The vast majority of PDAC cases are driven by activating mutations in the proto-oncogene KRAS, which results in constitutive proliferation and...

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Detalles Bibliográficos
Autores principales: Smigiel, Jacob M., Parameswaran, Neetha, Jackson, Mark W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789364/
https://www.ncbi.nlm.nih.gov/pubmed/29320425
http://dx.doi.org/10.3390/cancers10010014
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author Smigiel, Jacob M.
Parameswaran, Neetha
Jackson, Mark W.
author_facet Smigiel, Jacob M.
Parameswaran, Neetha
Jackson, Mark W.
author_sort Smigiel, Jacob M.
collection PubMed
description Mortality remains alarmingly high for patients diagnosed with pancreatic ductal adenocarcinoma (PDAC), with 93% succumbing to the disease within five years. The vast majority of PDAC cases are driven by activating mutations in the proto-oncogene KRAS, which results in constitutive proliferation and survival signaling. As efforts to target RAS and its downstream effectors continue, parallel research aimed at identifying novel targets is also needed in order to improve therapeutic options and efficacy. Recent studies demonstrate that self-renewing cancer stem cells (CSCs) contribute to metastatic dissemination and therapy failure, the causes of mortality from PDAC. Here, we discuss current challenges in PDAC therapeutics, highlight the contribution of mesenchymal/CSC plasticity to PDAC pathogenesis, and propose that targeting the drivers of plasticity will prove beneficial. Increasingly, intrinsic oncogenic and extrinsic pro-growth/survival signaling emanating from the tumor microenvironment (TME) are being implicated in the de novo generation of CSC and regulation of tumor cell plasticity. An improved understanding of key regulators of PDAC plasticity is providing new potential avenues for targeting the properties associated with CSC (including enhanced invasion and migration, metastatic outgrowth, and resistance to therapy). Finally, we describe the growing field of therapeutics directed at cancer stem cells and cancer cell plasticity in order to improve the lives of patients with PDAC.
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spelling pubmed-57893642018-02-02 Targeting Pancreatic Cancer Cell Plasticity: The Latest in Therapeutics Smigiel, Jacob M. Parameswaran, Neetha Jackson, Mark W. Cancers (Basel) Review Mortality remains alarmingly high for patients diagnosed with pancreatic ductal adenocarcinoma (PDAC), with 93% succumbing to the disease within five years. The vast majority of PDAC cases are driven by activating mutations in the proto-oncogene KRAS, which results in constitutive proliferation and survival signaling. As efforts to target RAS and its downstream effectors continue, parallel research aimed at identifying novel targets is also needed in order to improve therapeutic options and efficacy. Recent studies demonstrate that self-renewing cancer stem cells (CSCs) contribute to metastatic dissemination and therapy failure, the causes of mortality from PDAC. Here, we discuss current challenges in PDAC therapeutics, highlight the contribution of mesenchymal/CSC plasticity to PDAC pathogenesis, and propose that targeting the drivers of plasticity will prove beneficial. Increasingly, intrinsic oncogenic and extrinsic pro-growth/survival signaling emanating from the tumor microenvironment (TME) are being implicated in the de novo generation of CSC and regulation of tumor cell plasticity. An improved understanding of key regulators of PDAC plasticity is providing new potential avenues for targeting the properties associated with CSC (including enhanced invasion and migration, metastatic outgrowth, and resistance to therapy). Finally, we describe the growing field of therapeutics directed at cancer stem cells and cancer cell plasticity in order to improve the lives of patients with PDAC. MDPI 2018-01-10 /pmc/articles/PMC5789364/ /pubmed/29320425 http://dx.doi.org/10.3390/cancers10010014 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Smigiel, Jacob M.
Parameswaran, Neetha
Jackson, Mark W.
Targeting Pancreatic Cancer Cell Plasticity: The Latest in Therapeutics
title Targeting Pancreatic Cancer Cell Plasticity: The Latest in Therapeutics
title_full Targeting Pancreatic Cancer Cell Plasticity: The Latest in Therapeutics
title_fullStr Targeting Pancreatic Cancer Cell Plasticity: The Latest in Therapeutics
title_full_unstemmed Targeting Pancreatic Cancer Cell Plasticity: The Latest in Therapeutics
title_short Targeting Pancreatic Cancer Cell Plasticity: The Latest in Therapeutics
title_sort targeting pancreatic cancer cell plasticity: the latest in therapeutics
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789364/
https://www.ncbi.nlm.nih.gov/pubmed/29320425
http://dx.doi.org/10.3390/cancers10010014
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