Our recent studies have shown that hypothermic microenvironment promotes tumor progression and that the molecular sensors for cold are the transient receptor potential (TRP) channels TRPM8 and TRPA1. To evaluate the contribution of TRPM8 and TRPA1 to cancer malignancy, we screened cell subpopulations from Lewis lung cancer (LLC) using limiting dilutions and Western blotting. We identified that LLC-1 cells express 3-fold more TRPM8 than TRPA1, LLC-2 cells express TRPM8 at levels similar to TRPA1, and LLC-3 cells express TRPM8 at one-third the level of TRPA1. LLC-2 cells showed greater adhesion, migration, invasiveness and resistance to hypothermia than LLC-1 and LLC-3 cells, although LLC-2 cells had a longer doubling time. TRPM8 or TRPA1 knockdown using siRNA promoted cell proliferation and decreased adhesion and invasiveness in LLC-2 cells. When assessed for UCP2 staining, LLC-1 cells showed increased staining compared to LLC-2 cells, both of which had more UCP2-positive cells than the LLC-3 subpopulation. In an autophagy assay, hypothermia induced substantially less autophagy in LLC-1 cells than in LLC-2 cells, which displayed decreased autophagy compared to LLC-3 cells. Moreover, mice injected with LLC-2 cells had significantly more spontaneous and experimental lung metastases and a shorter overall survival time than mice injected with LLC-1 or LLC-3 cells. Importantly, LLC-2 cells were also more resistant to activated spleen CTL and the chemotherapeutic drug doxorubicin than LLC-1 and LLC-3 cells in vitro. Collectively, our data suggest that TRPM8 induces UCP2 to trigger metabolic transformation, whereas TRPA1 induces autophagy during adverse conditions, and the combination of both genes contributes directly to an invasive phenotype in lung cancer.
Microenvironment has been increasingly recognized as a critical regulator of cancer progression. In this study, we identified early changes in the microenvironment that contribute to malignant progression. Exposure of human bronchial epithelial cells (BEAS-2B) to methylnitrosourea (MNU) caused a reduction in cell toxicity and an increase in clonogenic capacity when the temperature was lowered from 37°C to 28°C. Hypothermia-incubated adipocyte media promoted proliferation in A549 cells. Although a hypothermic environment could increase urethane-induced tumor counts and Lewis lung cancer (LLC) metastasis in lungs of three breeds of mice, an increase in tumor size could be discerned only in obese mice housed in hypothermia. Similarly, coinjections using differentiated adipocytes and A549 cells promoted tumor development in athymic nude mice when adipocytes were cultured at 28°C. Conversely, fat removal suppressed tumor growth in obese C57BL/6 mice inoculated with LLC cells. Further studies show hypothermia promotes a MNU-induced epithelial-mesenchymal transition (EMT) and protects the tumor cell against immune control by TGF-β1 upregulation. We also found that activated adipocytes trigger tumor cell proliferation by increasing either TNF-α or VEGF levels. These results suggest that hypothermia activates adipocytes to stimulate tumor boost and play critical determinant roles in malignant progression.
Background Internal hospital infection is one of the major public health concerns worldwide. To investigate the etiological characteristics and risk factors of infections after colorectal cancer(CRC) surgery and the formulation of targeted infection control strategies. Methods This is a retrospective analysis of 1500 patients from colorectal cancer patients from General Surgery between March 2018 and March 2022,Anyang Tumor Hospital. Based on pathogen distribution and results of drug sensitivity testing, pattern of pathogens and drug resistance in infection in hospitalized patients with with colonic malignancy were analyzed. We conducted univariate and multivariate logistic regression analyses to determine the risk factors of infections that are associated with postoperative colorectal cancer. Results Infection cases were noted in 5.20% of all 1500 cases (78 of 1500 CRC patients). Drug resistance pattern showed that 88.89% of the implicated coagulase-negative staphylococci species and 40% of the implicated Acinetobacter species were meropenem-resistant. Considering all infection sites, age >60 years (OR=2.190, P=0.002), diabetes mellitus (OR=2.044, P=0.005), operation time >3h (OR=2.178, P=0.002) ), hospitalization time >10d (OR=1.793, P=0.017), parenteral nutrition (OR=2.797, P=0.000), indwelling catheter (OR=1.699, P=0.038), mechanical ventilation (OR=2.294, P=0.001) and the usage of drainage tube (OR=3.455, P=0.000) were risk factors at multivariate analysis. Conclusions: Post-operative infections may negatively affect surgical outcomes. Based on the greatest available evidence,important preoperative risk factors for postoperative colorectal cancer infections have been identified. Knowledge on risk factors may influence treatment and procedure-related decisions, and possibly reduce the postoperative infection rate.
purpose:As part of supportive therapy, prophylaxis with tiopronin for injection (TI) against common hepatotoxicity complications has often been used. However, methods to prevent hepatotoxicity have not been established. Therefore, we analyzed the relationship between the periods of TI prophylaxis and its efficacy in preventing hepatotoxicity,evaluate the value of prolonging the duration of TI administration in preventing hepatotoxicity in gynecological cancer patients. Methods This is a retrospective study. During 2022.1–2023.3, 452 patients with gynecological cancer patients were included in this study,the patient had normal liver function tests before treatment. The influencing factors of liver toxicity after treatment were analyzed, and different subgroups were divided according to the influencing factors. In total sample and different subgroups, we evaluated the prophylactic efficacy of TI by comparing the number of days of TI use. and the difference of the number of days of TI use on the prognosis of patients was compared in the total samples. Results In total samples, there was no significant difference the effectiveness of TI with different prevention days for hepatotoxicity (P>0.05), and there was no significant difference in prognosis of tumor (P>0.05). The influencing factors of hepatotoxicity were the combinations of chemotherapeutic drugs,duration of chemotherapy drug use and the previous hepatotoxicity of patients. In different subgroups, there was no significant difference the effectiveness of TI with different prevention days for hepatotoxicity (P>0.05). Conclusion TI is used as prophylactic drug in gynecological cancers, and prolonging periods of administration has no clinical value in preventing hepatotoxicity.
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