Cyclooxygenases and Prostaglandins in Tumor Immunology and Microenvironment of Gastrointestinal Cancer

Wang, Dingzhi; Cabalag, Carlos S.; Clemons, Nicholas J.; DuBois, Raymond N.

doi:10.1053/j.gastro.2021.09.059

Cited by 84 publications

(63 citation statements)

References 178 publications

(190 reference statements)

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“…Whether the observed COX-2-mediated inflammatory effects of CTX-treated dying cancer cells promote or hinder CTX efficacy cannot be easily inferred. PGE 2 can have pleiotropic and often contrasting effects on the immune system 52 , 53 , recently implicated both in subverting anti-tumor immunity 27 – 30 as well as promoting immunosurveillance of senescent cells and suppression of early tumorigenesis 54 . Additionally the contribution of myeloid cells, such as neutrophils, to the efficacy of cytotoxic therapy is also conflicted 55 .…”

Section: Discussionmentioning

confidence: 99%

Chemotherapy-induced COX-2 upregulation by cancer cells defines their inflammatory properties and limits the efficacy of chemoimmunotherapy combinations

et al. 2022

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Cytotoxic therapies, besides directly inducing cancer cell death, can stimulate immune-dependent tumor growth control or paradoxically accelerate tumor progression. The underlying mechanisms dictating these opposing outcomes are poorly defined. Here, we show that cytotoxic therapy acutely upregulates cyclooxygenase (COX)-2 expression and prostaglandin E2 (PGE2) production in cancer cells with pre-existing COX-2 activity. Screening a compound library of 1280 approved drugs, we find that all classes of chemotherapy drugs enhance COX-2 transcription whilst arresting cancer cell proliferation. Genetic manipulation of COX-2 expression or its gene promoter region uncover how augmented COX-2/PGE2 activity post-treatment profoundly alters the inflammatory properties of chemotherapy-treated cancer cells in vivo. Pharmacological COX-2 inhibition boosts the efficacy of the combination of chemotherapy and PD-1 blockade. Crucially, in a poorly immunogenic breast cancer model, only the triple therapy unleashes tumor growth control and significantly reduces relapse and spontaneous metastatic spread in an adjuvant setting. Our findings suggest COX-2/PGE2 upregulation by dying cancer cells acts as a major barrier to cytotoxic therapy-driven tumor immunity and uncover a strategy to improve the outcomes of immunotherapy and chemotherapy combinations.

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Section: Discussionmentioning

confidence: 99%

Chemotherapy-induced COX-2 upregulation by cancer cells defines their inflammatory properties and limits the efficacy of chemoimmunotherapy combinations

et al. 2022

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“…In addition, swimming affected the expression of cyclooxygenase-2 (COX-2) in the colon. The expression of COX-2, one of inflammation-related enzyme and exercise-induced expression alteration biomarkers (9,30), was upregulated in mucosal surfacing by AOM/DSS in Modle group (Figure 2H, Model), and was down in Swimming pretreatment group (Figure 2H, Model_Swim).…”

Section: Swimming Pretreatment Attenuates Aom/ Dss-induced Tumor Deve...mentioning

confidence: 99%

“…We therefore have more chances of discovering the risk factors of CRC and precancerous lesions early, intervening and treating them in time to reverse the development of the tumors. It is widely accepted that chronic inflammation has long been recognized as a crucial trigger of somatic tumorigenesis and progression (7)(8)(9). CRC can be categorized as two types: colitis-associated cancer (CAC) and sporadic CRC.…”

Section: Introductionmentioning

confidence: 99%

Swimming Impedes Intestinal Microbiota and Lipid Metabolites of Tumorigenesis in Colitis-Associated Cancer

Wang

Xu²,

Chu³

et al. 2022

Front. Oncol.

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BackgroundAccumulating data support that regular physical activity potentially inhibits chronic colitis, a risk factor for colitis-associated cancer (CAC). However, possible effects of physical activity on CAC and the underlying mechanisms remain poorly understood.MethodsA pretreatment of swimming on azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CAC mice was implemented to determine its protective effect. Inflammation and tumorigenesis were assessed using colorectums from C57BL/6 mice. In order to determine how swimming alters colonic lipid metabolism and gene expression, a comparative analysis was conducted. Meanwhile, alterations in intestinal microbiota and short-chain fatty acids (SCFAs) were detected and analyzed. Finally, an integration analysis of colonic lipid metabolism with gene expression and intestinal microbiota was performed respectively.ResultSwimming pretreatment relieved bowel inflammation and minimized tumor formation. We demonstrated that prostaglandin E2 (PGE2)/PGE2 receptor 2 subtype (EP2) signaling as a potential regulatory target for swimming induces colonic lipid metabolites. Swimming-induced genera, Erysipelatoclostridium, Parabacteroides, Bacteroides, and Rikenellaceae_RC9_gut_group, induced intestinal SCFAs and affected the function of colonic lipid metabolites enriched in glycerophospholipid metabolism and choline metabolism in cancer.ConclusionAccording to our experiments, swimming pretreatment can protect mice from CAC by intervention in the possible link between colonic lipid metabolites and PGE2/EP2 signaling. Further, swimming-induced genera and probiotics promoted glycerophospholipid metabolism and choline metabolism in cancer, the major constituents of colonic lipid metabolites, and increased SCFAs, which were also important mechanisms for the anti-inflammatory and anti-tumorigenic effects of swimming.

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“…Environmental factors, Helicobacter pylori infection, smoking, and lifestyle play major roles in stomach cancer. At present, although the research on gastric cancer has achieved great success, the molecular mechanism of gastric cancer is still not fully understood, and the effective treatment of gastric cancer is still a hot issue [ 2 , 3 ]. Abnormal expression of CDK6 affects the initiation and progression of various malignant tumors [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Expression of CDK6 in Stomach Cancer and the Effect of CDK4/6 Inhibitor PD-0332991 on the Function of Stomach Cancer Cells

Liu

Zhao

Han

et al. 2022

Computational and Mathematical Methods in Medicine

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Objective. To study the expression and prognostic value of CDK6 in stomach cancer and the function of CDK4/6 inhibitor PD-0332991 on the proliferation of stomach cancer cells. Methods. Immunohistochemistry was used to detect the expression of CDK6 in stomach cancer tissues and adjacent normal tissues and to analyze the effect of CDK6 on clinicopathological parameters of stomach cancer patients. Kaplan-Meier plotter was employed to study the relationship between CDK6 and overall survival in stomach cancer. Western blot and RT-PCR were used to detect protein and gene expression of CDK6 in different cells. The effects of CDK4/6 inhibitor PD-0332991 on apoptosis and aging of stomach cancer cells were detected by flow cytometry and β-galactosidase aging staining assay. The effects of CDK4/6 inhibitor PD-0332991 on the invasion and migration of stomach cancer cells were explored by the wound healing experiment and the Transwell experiment. The supernatant of stomach cancer cells was collected, and the effect of CDK4/6 inhibitor PD-0332991 on tumor markers of stomach cancer cells was detected by biochemical immunoassay. Results. (1) CDK6 was highly expressed in stomach cancer tissues and cells. (2) Abnormally elevated CDK6 expression results in shorter survival in stomach cancer patients. (3) CDK4/6 inhibitor PD-0332991 could block the proliferation of stomach cancer cells, but not stomach epithelial proliferation. PD-0332991 could inhibit the secretion of pro-GRP by MGC 823. (4) PD-0332991 could advance the development of the apoptosis and senescence of stomach cancer cells and suppressed the invasion and migration of stomach cancer cells. Conclusion. CDK6 expression is elevated in gastric cancer, and the CDK4/6 inhibitor PD-0332991 can remarkably promote apoptosis and senescence of stomach cancer cells and effectively inhibit the migration and invasion of stomach cancer cells.

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Cyclooxygenases and Prostaglandins in Tumor Immunology and Microenvironment of Gastrointestinal Cancer

Cited by 84 publications

References 178 publications

Chemotherapy-induced COX-2 upregulation by cancer cells defines their inflammatory properties and limits the efficacy of chemoimmunotherapy combinations

Chemotherapy-induced COX-2 upregulation by cancer cells defines their inflammatory properties and limits the efficacy of chemoimmunotherapy combinations

Swimming Impedes Intestinal Microbiota and Lipid Metabolites of Tumorigenesis in Colitis-Associated Cancer

Expression of CDK6 in Stomach Cancer and the Effect of CDK4/6 Inhibitor PD-0332991 on the Function of Stomach Cancer Cells

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