TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3

Hesler, Rachel; Huang, Jennifer; Starr, Mark D.; Treboschi, Victoria; Bernanke, Alyssa G.; Nixon, Andrew B.; McCall, Shannon J.; White, Rebekah R.; Blobe, Gerard C.

doi:10.1093/carcin/bgw093

Cited by 69 publications

(56 citation statements)

References 63 publications

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“…The failure of gemcitabine to attack aggressive pancreatic cancers cells is due to intrinsic (metabolic malfunction) or extrinsic resistance (drug delivery/ desmoplasia) or both to gemcitabine (9,15,47). Thus, multiple studies have been carried out to understand the mechanism, and they gave new insights into the gemcitabine resistance of aggressive cancer cells having cancer stem cell-like properties (47,(49)(50)(51). These studies, collectively, suggested that simultaneously targeting intrinsic-and extrinsic-resistant events may increase the toxic effects of gemcitabine and increase patient survival.…”

Section: Discussionmentioning

confidence: 99%

CYR61/CCN1 Regulates dCK and CTGF and Causes Gemcitabine-resistant Phenotype in Pancreatic Ductal Adenocarcinoma

Maity

Ghosh

Gupta

et al. 2019

Molecular Cancer Therapeutics

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Pancreatic ductal adenocarcinoma (PDAC) develops extrinsic-and intrinsic-resistant phenotypes to prevent chemotherapies from entering into the cells by promoting desmoplastic reactions (DR) and metabolic malfunctions of the drugs. It is well established that these responses are also associated with pancreatic cancer cells' gemcitabine resistance. However, the mechanism by which these resistant pathways function in the pancreatic cancer cells remains poorly understood. In these studies, we show that CYR61/ CCN1 signaling plays a vital role in making pancreatic cancer cells resistant to gemcitabine in vitro and also in a tumor xenograft model. We proved that the catastrophic effect of gemcitabine could significantly be increased in gemcitabineresistant PDAC cells when CYR61/CCN1 is depleted, while this effect can be suppressed in gemcitabine-sensitive neoplastic cells by treating them with CYR61/CCN1 recombinant protein. Ironically, nontransformed pancreatic cells, which are sensitive to gemcitabine, cannot be resistant to gemcitabine by CYR61/CCN1 protein treatment, showing a unique feature of CYR61/CCN signaling that only influences PDAC cells to become resistant. Furthermore, we demonstrated that CYR61/CCN1 suppresses the expression of the gemcitabineactivating enzyme deoxycytidine kinase (dCK) while it induces the expression of a DR-promoting factor CTGF (connective tissue growth factor) in pancreatic cancer cells in vitro and in vivo. Thus, the previously described mechanisms (dCK and CTGF pathways) for gemcitabine resistance may be two novel targets for CYR61/CCN1 to protect pancreatic cancer cells from gemcitabine. Collectively, these studies reveal a novel paradigm in which CYR61/CCN1regulates both extrinsic and intrinsic gemcitabine resistance in PDAC cells by employing unique signaling pathways.

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Section: Discussionmentioning

confidence: 99%

CYR61/CCN1 Regulates dCK and CTGF and Causes Gemcitabine-resistant Phenotype in Pancreatic Ductal Adenocarcinoma

Maity

Ghosh

Gupta

et al. 2019

Molecular Cancer Therapeutics

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“…Zechner et al did find that, within primary tumors treated with a combination of metformin and gemcitabine, metformin better inhibited cancer cells near the desmoplastic stroma, whereas gemcitabine inhibited proliferation in cells distant to the stroma [48]. Hesler et al showed that CAFs serve as sources of CYR61 in co-culture models and induce chemoresistance by downregulating nucleoside transporters that mediate cellular uptake of gemcitabine [49]. Together, these studies indicate that further research is needed to understand the ability of PDAC to develop chemoresistance in order to either exploit or overcome the stromal component of the tumor.…”

Section: Role Of Stromal Cells In Chemoresistancementioning

confidence: 99%

The role of stromal cancer-associated fibroblasts in pancreatic cancer

et al. 2017

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Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer generally refractory to conventional treatments. Cancer-associated fibroblasts (CAFs) are cellular components of the desmoplastic stroma characteristic to the tumor that contributes to this treatment resistance. Various markers for CAFs have been explored including palladin and CD146 that have prognostic and functional roles in the pathobiology of PDAC. Mechanisms of CAF-tumor cell interaction have been described including exosomal transfer and paracrine signaling mediated by cytokines such as GM-CSF and IL-6. The role of downstream signaling pathways including JAK/STAT, mTOR, sonic hedge hog (SHH), and NFkB have also been shown to play an important function in PDAC-CAF cross talk. The role of autophagy and other metabolic effects on each cell type within the tumor have also been proposed to play roles in facilitating CAF secretory function and enhancing tumor growth in a low-glucose microenvironment. Targeting the stroma has gained interest with multiple preclinical and clinical trials targeting SHH, JAK2, and methods of either exploiting the secretory capability of CAFs to enhance drug delivery or inhibiting it to prevent its influence on cancer cell chemoresistance. This review summarizes the most recent progress made in understanding stromal formation; its contribution to tumor proliferation, invasion, and metastasis; its role in chemoresistance; and potential therapeutic strategies on the horizon.

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“…The correction or deletion of resistance‐related genes is a promising development for tumor therapy. Current studies on drug resistance of tumor cells using CRISPR/Cas9 in lung cancer, breast cancer, melanoma, urogenital tumors, and gastrointestinal tumors about chemotherapy drugs, targeted drugs, and inhibitors were summarized in Table . Besides the above‐mentioned studies, there are other studies on the mechanisms related to drug resistance of other malignant tumors cells by using CRISPR/Cas9.…”

Section: Using Crispr/cas9 In the Study Of Tumor Therapiesmentioning

confidence: 99%

“…Current studies on drug resistance of tumor cells using CRISPR/Cas9 in lung cancer, breast cancer, melanoma, urogenital tumors, and gastrointestinal tumors about chemotherapy drugs, targeted drugs, and inhibitors were summarized in Table 2. 56,88,94,97,100,113,[141][142][143][144][145][146][147][148][149][150][151][152][153][154][155] Compared with wild-type cells, ATG5 KO cells had stronger migration ability and significantly increased resistance to the Src tyrosine kinase inhibitor PP2. 156 The results showed that autophagy deficiency can induce malignant cell transformation and resistance to PP2.…”

Section: Drug Resistance Study Of Tumorsmentioning

confidence: 99%

Application of CRISPR/Cas9 gene editing technique in the study of cancer treatment

et al. 2019

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In recent years, gene editing, especially that using clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9, has made great progress in the field of gene function. Rapid development of gene editing techniques has contributed to their significance in the field of medicine. Because the CRISPR/Cas9 gene editing tool is not only powerful but also has features such as strong specificity and high efficiency, itcan accurately and rapidly screen the whole genome, facilitating the administration of gene therapy for specific diseases. In the field of tumor research, CRISPR/Cas9 can be used to edit genomes to explore the mechanisms of tumor occurrence, development, and metastasis. In these years, this system has been increasingly applied in tumor treatment research. CRISPR/Cas9 can be used to treat tumors by repairing mutations or knocking out specific genes. To date, numerous preliminary studies have been conducted on tumor treatment in related fields. CRISPR/Cas9 holds great promise for gene-level tumor treatment. Personalized and targeted therapy based on CRISPR/Cas9 will possibly shape the development of tumor therapy in the future. In this study, we review the findings of CRISPR/Cas9 for tumor treatment research to provide references for related future studies on the pathogenesis and clinical treatment of tumors.

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TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3

Cited by 69 publications

References 63 publications

CYR61/CCN1 Regulates dCK and CTGF and Causes Gemcitabine-resistant Phenotype in Pancreatic Ductal Adenocarcinoma

CYR61/CCN1 Regulates dCK and CTGF and Causes Gemcitabine-resistant Phenotype in Pancreatic Ductal Adenocarcinoma

The role of stromal cancer-associated fibroblasts in pancreatic cancer

Application of CRISPR/Cas9 gene editing technique in the study of cancer treatment

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