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Stellate Cells Aid Growth-Permissive Metabolic Reprogramming and Promote Gemcitabine Chemoresistance in Pancreatic Cancer

by 1,2,* and 2,3
1
Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, 0316 Oslo, Norway
2
Department of Hepato-Pancreato-Biliary Surgery, Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway
3
Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital Rikshospitalet, 0424 Oslo, Norway
*
Author to whom correspondence should be addressed.
Academic Editor: Hidekazu Suzuki
Cancers 2021, 13(4), 601; https://doi.org/10.3390/cancers13040601
Received: 15 December 2020 / Revised: 4 January 2021 / Accepted: 29 January 2021 / Published: 3 February 2021
The great majority, more than 90%, of patients with pancreatic ductal adenocarcinoma (PDAC) die within less than five years after detection of the disease, despite recent treatment advances. The poor prognosis is related to late diagnosis, aggressive disease progression, and tumor resistance to conventional chemotherapy. PDAC tumor tissue is characterized by dense fibrosis and poor nutrient availability. A large portion of the tumor is made up of stromal fibroblasts, the pancreatic stellate cells (PSCs), which are known to contribute to tumor progression in several ways. PSCs have been shown to act as an alternate energy source, induce drug resistance, and inhibit drug availability in tumor cells, however, the underlying exact molecular mechanisms remain unknown. In this literature review, we discuss recent available knowledge about the contributions of PSCs to the overall progression of PDAC via changes in tumor metabolism and how this is linked to therapy resistance.
Pancreatic ductal adenocarcinoma (PDAC), also known as pancreatic cancer (PC), is characterized by an overall poor prognosis and a five-year survival that is less than 10%. Characteristic features of the tumor are the presence of a prominent desmoplastic stromal response, an altered metabolism, and profound resistance to cancer drugs including gemcitabine, the backbone of PDAC chemotherapy. The pancreatic stellate cells (PSCs) constitute the major cellular component of PDAC stroma. PSCs are essential for extracellular matrix assembly and form a supportive niche for tumor growth. Various cytokines and growth factors induce activation of PSCs through autocrine and paracrine mechanisms, which in turn promote overall tumor growth and metastasis and induce chemoresistance. To maintain growth and survival in the nutrient-poor, hypoxic environment of PDAC, tumor cells fulfill their high energy demands via several unconventional ways, a process generally referred to as metabolic reprogramming. Accumulating evidence indicates that activated PSCs not only contribute to the therapy-resistant phenotype of PDAC but also act as a nutrient supplier for the tumor cells. However, the precise molecular links between metabolic reprogramming and an acquired therapy resistance in PDAC remain elusive. This review highlights recent findings indicating the importance of PSCs in aiding growth-permissive metabolic reprogramming and gemcitabine chemoresistance in PDAC. View Full-Text
Keywords: pancreatic cancer; pancreatic stellate cell; metabolic reprogramming; gemcitabine chemoresistance pancreatic cancer; pancreatic stellate cell; metabolic reprogramming; gemcitabine chemoresistance
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MDPI and ACS Style

Amrutkar, M.; Gladhaug, I.P. Stellate Cells Aid Growth-Permissive Metabolic Reprogramming and Promote Gemcitabine Chemoresistance in Pancreatic Cancer. Cancers 2021, 13, 601. https://doi.org/10.3390/cancers13040601

AMA Style

Amrutkar M, Gladhaug IP. Stellate Cells Aid Growth-Permissive Metabolic Reprogramming and Promote Gemcitabine Chemoresistance in Pancreatic Cancer. Cancers. 2021; 13(4):601. https://doi.org/10.3390/cancers13040601

Chicago/Turabian Style

Amrutkar, Manoj, and Ivar P. Gladhaug. 2021. "Stellate Cells Aid Growth-Permissive Metabolic Reprogramming and Promote Gemcitabine Chemoresistance in Pancreatic Cancer" Cancers 13, no. 4: 601. https://doi.org/10.3390/cancers13040601

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