iNOS Regulates the Therapeutic Response of Pancreatic Cancer Cells to Radiotherapy

Pereira, Patrícia M. R.; Edwards, Kimberly J.; Mandleywala, Komal; Carter, Lukas M.; Escorcia, Freddy E.; Campesato, Luís Felipe; Cornejo, Mike; Abma, Lolkje; Mohsen, Abu Akeel; Iacobuzio-Donahue, Christine A.; Merghoub, Taha; Lewis, Jason S.

doi:10.1158/0008-5472.can-19-2991

Cited by 36 publications

(34 citation statements)

References 62 publications

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“…Benkhelifa et al observed that significantly increased iNOS mRNA expression in metastatic tissues of colorectal cancer compared to primary tumors and unaffected mucosa [ 19 ]. Pereira et al showed that iNOS expressions were significantly increased in cancer-associated fibroblasts in pancreatic ductal adenocarcinoma [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

iNOS Promotes the Development of Osteosarcoma via Wnt/β-Catenin Pathway

Chu

Cao

Daokun³

et al. 2021

Journal of Immunology Research

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Inducible nitric oxide synthase (iNOS), accompanied with protumor and antitumor activity, has been studied in multiple cancers. However, the role of iNOS expression in osteosarcoma (OS) is far from being fully understood. In present work, iNOS levels were detected in OS tissues and cell lines. Colony formation assay, Transwell assay, and fow cytometer were used to assess proliferation, migration, invasion, and apoptosis abilities in vitro after iNOS inhibition. Western blotting determined the expressions of iNOS, MMP2, MMP9, C-MYC, Ki67, PCNA, and β-catenin. Mice transfected with OS cells were to evaluate tumor formation. IHC assay was to evaluate the expressions of iNOS and β-catenin in mice. The results showed that iNOS was upregulated in both OS tissues and cells compared with that in matched normal tissues or cells. And we found that proliferation, migration, and invasion numbers of OS cells were decreased, and apoptosis numbers of OS cells were increased after iNOS inhibition. MMP2, MMP9, C-MYC, Ki67, and PCNA levels were also reduced in OS cells treated with iNOS inhibition. Else, iNOS inhibition would suppress β-catenin expression in OS cells to regulate MMP2, MMP9, C-MYC, Ki67, and PCNA expressions. In addition, tumor formation, iNOS expression, and β-catenin expression were inhibited in mice transplanted with iNOS knockout OS cells. These results indicated that iNOS might be a potential therapeutic target for OS.

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Section: Discussionmentioning

confidence: 99%

iNOS Promotes the Development of Osteosarcoma via Wnt/β-Catenin Pathway

Chu

Cao

Daokun³

et al. 2021

Journal of Immunology Research

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“…Results from these studies indicate an influx in suppressive macrophages, Tregs and increases in inducible Nitic Oxide Synthase (iNOS) release by cancer-associated fibroblasts that together result in poor T-cell activity and sparse infiltration of pancreatic tumor tissues. [76][77][78] In contrast, chemotherapy is hypothesized to increase T-cell priming, which we discuss further briefly, and data from our group and others indeed suggest immune changes elicited by chemotherapy are significant. 76 79 Thus, considering how immunotherapy approaches can be strategically combined with radiation or chemotherapy will be key in moving forward.…”

Section: Therapeutic Approaches To Ameliorate T-cell Exclusion and Inmentioning

confidence: 77%

Mirage or long-awaited oasis: reinvigorating T-cell responses in pancreatic cancer

Ware

El‐Rayes

Lesinski

2020

J Immunother Cancer

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Pancreatic ductal adenocarcinoma (PDAC) is plagued by a dismal 5-year survival rate, early onset of metastasis and limited efficacy of systemic therapies. This scenario highlights the need to fervently pursue novel therapeutic strategies to treat this disease. Recent research has uncovered complicated dynamics within the tumor microenvironment (TME) of PDAC. An abundant stroma provides a framework for interactions between cancer-associated fibroblasts, suppressive myeloid cells and regulatory lymphocytes, which together create an inhospitable environment for adaptive immune responses. This accounts for the poor infiltration and exhausted phenotypes of effector T cells within pancreatic tumors. Innovative studies in genetically engineered mouse models have established that with appropriate pharmacological modulation of suppressive elements in the TME, T cells can be prompted to regress pancreatic tumors. In light of this knowledge, innovative combinatorial strategies involving immunotherapy and targeted therapies working in concert are rapidly emerging. This review will highlight recent advances in the field related to immune suppression in PDAC, emerging preclinical data and rationale for ongoing immunotherapy clinical trials. In particular, we draw attention to foundational findings involving T-cell activity in PDAC and encourage development of novel therapeutics to improve T-cell responses in this challenging disease.

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“…Similarly, in a model of pancreatic ductal adenocarcinoma, conditioned medium from irradiated fibroblasts (5 Gy) increases iNOS/NO signaling in cancer cells, activating the production of pro-inflammatory cytokines through NF-kB signaling. The activation of this pathway increases cancer cell aggressiveness, with higher cell growth, migration invasion and metastatic potential (118). CAFs promote cancer cell aggressiveness also by secreting factors that induce EMT.…”

Section: Fibroblasts and Mesenchymal Stem Cellsmentioning

confidence: 99%

Radiation-Induced Immunity and Toxicities: The Versatility of the cGAS-STING Pathway

et al. 2021

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In the past decade, radiation therapy (RT) entered the era of personalized medicine, following the striking improvements in radiation delivery and treatment planning optimization, and in the understanding of the cancer response, including the immunological response. The next challenge is to identify the optimal radiation regimen(s) to induce a clinically relevant anti-tumor immunity response. Organs at risks and the tumor microenvironment (e.g. endothelial cells, macrophages and fibroblasts) often limit the radiation regimen effects due to adverse toxicities. Here, we reviewed how RT can modulate the immune response involved in the tumor control and side effects associated with inflammatory processes. Moreover, we discussed the versatile roles of tumor microenvironment components during RT, how the innate immune sensing of RT-induced genotoxicity, through the cGAS-STING pathway, might link the anti-tumor immune response, radiation-induced necrosis and radiation-induced fibrosis, and how a better understanding of the switch between favorable and deleterious events might help to define innovative approaches to increase RT benefits in patients with cancer.

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iNOS Regulates the Therapeutic Response of Pancreatic Cancer Cells to Radiotherapy

Abstract: and Aprea. He has patents on applications related to work on oncolytic viral therapy, alpha virus-based vaccine, neo antigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. Research.

Cited by 36 publications

References 62 publications

iNOS Promotes the Development of Osteosarcoma via Wnt/β-Catenin Pathway

iNOS Promotes the Development of Osteosarcoma via Wnt/β-Catenin Pathway

Mirage or long-awaited oasis: reinvigorating T-cell responses in pancreatic cancer

Radiation-Induced Immunity and Toxicities: The Versatility of the cGAS-STING Pathway

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