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Vascular endothelial growth factor (VEGF) plays an important role in promoting tumor vascular growth and changing vascular wall permeability. With the in-depth study of tumor hyperthermia and tumor microenvironment, more and more studies have shown that hyperthermia exerts multiple regulatory effects on VEGF in tumor microenvironment. Combined with current research progress in China and abroad, this article reviews the effect of hyperthermia on VEGF and its related cells and factors in tumor microenvironment, aiming to provide new ideas for the clinical application of tumor hyperthermia combined with immune or targeted therapy.
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Objective:To investigate the regulation and possible mechanism of hyperthermia (HT) on the ferroptosis of squamous cell carcinoma of the tongue cell line CAL-27.Methods:Half maximal inhibitory concentration (IC 50) of Fer-1, an inhibitor of ferroptosis, was detected by CCK-8 assay and used for subsequent experiments. CAL-27 cells were divided into the HT, control, Fer-1 and HT+ Fer-1 groups according to experimental design. Reactive oxygen species (ROS) levels and iron ion concentration were determined by corresponding detection kits. The p53 and TfR1 mRNA levels were detected by real-time reverse transcription PCR. Cell migration was detected by cell scratch test and cell apoptosis was detected by flow cytometry. Results:HT significantly up-regulated the ROS levels ( P<0.01) and iron ion concentration ( P<0.001), and significantly increased the expression levels of p53 and TfR1 mRNA (both P<0.01). The cell migration ability was decreased ( P<0.001), whereas cell apoptosis rate was increased by HT ( P<0.01). In the HT+Fer-1 group, the ROS levels ( P<0.001), iron ion concentration ( P<0.001), expression levels of p53 and TfR1 mRNA (both P<0.01) were significantly down-regulated, the cell migration ability was recovered ( P<0.01), and cell apoptosis rate was decreased ( P<0.01) compared with those in the HT group, respectively. Conclusions:HT may induce the ferroptosis of CAL-27 cell line, inhibit cell migration ability and promote cell apoptosis by activating the p53/TfR1 pathway.
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Objective:To observe the effect of hyperthermia combined with paclitaxel on the proliferation, apoptosis and cycle of human tongue squamous cell carcinoma cell line CAL-27, and to explore the underlying mechanism.Methods:The working concentration of paclitaxel was determined by CCK-8 assay, and the cultured CAL-27 cells were divided into the control, paclitaxel, 42℃ hyperthermia and combined treatment groups. The ability of cell proliferation was detected by colony formation assay, and the cell cycle and apoptosis were determined by flow cytometry. The expression levels of AKT, p-AKT, Bcl-2 and Bax proteins in each group were measured by Western blot.Results:Compared with the control group, the proliferation was significantly inhibited and the apoptosis of CAL-27 cells was significantly promoted in the combined treatment, hyperthermia and paclitaxel groups (all P<0.05), and the anti-proliferation and apoptosis-promoting effect in the combined treatment group was significantly better than those in the hyperthermia and paclitaxel groups (all P<0.05). Western blot showed that hyperthermia combined with paclitaxel could significantly up-regulate the expression level of Bax protein and significantly down-regulate the expression levels of P-AKT and Bcl-2 in CAL-27 cells (all P<0.05). Conclusions:Hyperthermia combined with paclitaxel can play a synergistic role in inhibiting proliferation and promoting apoptosis of tongue squamous cell carcinoma CAL-27 cells. The mechanism may be related to the inhibition of AKT activation and the activation of Bax/Bcl-2 apoptosis signaling pathway.
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In recent years, tumor hyperthermia has become a hot research topic as an adjuvant therapy to traditional tumor therapy. Hyperthermia can directly induce tumor cell necrosis or apoptosis, or inhibit tumor progression by destroying tumor blood vessels. Meantime, it can also activate the response of immune cells and cytokines in the immune system of the host, thereby regulating the immune state of tumor microenvironment. Multiple combined effects influence the tumor progression. A thorough understanding of the biological mechanism of hyperthermia is beneficial to the development of novel therapeutic methods. In this paper, the biological mechanism of hyperthermia in killing tumors was mainly reviewed.
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Objective:The investigate the roles and significance of HIF-1α and CYPJ in tongue squamous cell carcinoma cell (TSCC), and further evaluate the regulatory effect of hyperthermia (HT) on HIF-1α and CYPJ in TSCC cells.Methods:Eighty samples of cancer tissues and adjacent normal tissues from TSCC patients were collected. The expression levels of HIF-1α and CYPJ were detected by immunohistochemistry, Western blotting (WB) and fluorescence quantitative PCR, and the relationship between the expression levels of HIF-1α and CYPJ and clinicopathological characteristics was further analyzed. The expression levels of HIF-1α and CYPJ in Cal-27 cells under normoxic and hypoxic conditions for 24 h when combined with HT (42℃), chemotherapy and both were detected by qPCR and WB. Cell migration was detected by cell scratch test and cell apoptosis was measured by flow cytometry.Results:The expression levels of HIF-1α and CYPJ proteins in the tumor tissues of TSCC patients were higher than those in the adjacent normal tissues, which were significantly correlated with tumor size, TNM stage, differentiation degree and lymph node metastasis in TSCC patients (all P<0.05), whereas they were not correlated with gender or age (all P>0.05). The expression levels of HIF-1α and CYPJ in Cal-27 cells were significantly up-regulated in the hypoxic microenvironment (both P<0.05), which were also significantly enhanced by hyperthermia alone (both P<0.05). Compared with hyperthermia or chemotherapy alone, hyperthermia combined with chemotherapy significantly inhibited the expression of HIF-1α and CYPJ, suppressed cell migration and promoted cell apoptosis (all P<0.05). Conclusions:HIF-1α and CYPJ may be potential biomarkers for TSCC tumorigenicity and prognosis. In addition, tumor recurrence after hyperthermia may be due to the role of hyperthermia in triggering HIF-1α expression, which promotes the growth and survival of tumor cells adaptive to hyperthermia treatment by activating the downstream target genes, while hyperthermia combined with chemotherapy may be a promising treatment for TSCC.
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Metabolic reprogramming is a malignancy hallmark, which refers to the ability of cancer cells to alter metabolic and nutrient acquisition modes in order to support the energy demands for accomplishing the rapid growth, dissemination, metastasis and obtain the "building blocks" needed to maintain cell division. When solid tumors are exposed to low pH, low oxygen and tumor microenvironment with nutrient deficiencies, the hypoxia-inducible factor-1 can be activated, which mediates the remodeling of metabolic patterns in tumor cells, namely, energy is obtained by circulating intracellular components (removing substrates such as proteins and lipid) or by utilizing adaptive metabolic reprogramming (such as glycolysis, autophagy and lipid metabolism, etc.). As a treatment scheme based on local heating of tumors, hyperthermia has a variety of anticancer mechanisms and can be used in combination with radiotherapy, chemotherapy and biological immune therapy. In this review, we briefly discussed the metabolic remodeling model mediated by hypoxia-inducible factor 1 in a hypoxia microenvironment, described the possible regulatory mechanism of hyperthermia on hypoxia-inducible factor-1 and prospected the application of hyperthermia in oral and maxillofacial tumors.
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With the in-depth study of tumor hyperthermia and tumor immune microenvironment (TIME), the role of hyperthermia in TIME has captivated increasing attention from scholars in recent years. Based upon recent research progress at home and abroad, the effect and mechanism of hyperthermia on several major immune cells and immune-related cytokines in the TIME were reviewed in this article. Comprehensive and deep understanding of the regulation of hyperthermia on the TIME could provide new ideas and methods for tumor treatment.