Cancer pathogenesis and therapy最新文献

Background

Colon cancer is one of the most prevalent digestive cancers worldwide. Results of epidemiological, experimental, and clinical studies suggest that aspirin inhibits the development of colon cancer. This study aimed to systematically elucidate the molecular mechanisms by which aspirin prevents colon carcinogenesis.

Methods

We determined the global protein expression profiles of colorectal cancer and aspirin-treated cells using quantitative proteomic analysis. We analyzed the proteomic results using bioinformatics (including differential proteins, protein annotation, Kyoto Encyclopedia of Genes and Genomes [KEGG] pathways, and protein–protein interaction [PPI] network). The viability of the colon cancer cell line and HT29 ​cells treated with aspirin was determined using the cell counting kit-8 assay. The differentially expressed proteins, such as p53 and cyclin-dependent kinase 1 (CDK1), were quantified using real-time polymerase chain reaction (PCR) and Western blotting. We measured cell cycle distribution and apoptosis in HT29 ​cells exposed to aspirin using fluorescence-activated cell sorting (FACS).

Results

We found that 552 proteins were significantly dysregulated, of which 208 and 334 were upregulated and downregulated, respectively, in colon cancer cells exposed to 10 ​mmol/L of aspirin (95% confidence interval [CI]: -1.269 to -0.106, P ​< ​0.05). Further gene enrichment analysis revealed that cell cycle-related proteins, such as p53 and CDK1, were significantly differentially expressed. Proteomic analysis showed that after 24 ​h of aspirin exposure, the level of p53 increased by 2.52-fold and CDK1 was downregulated to half that of the controls in HT29 ​cells (95% CI: -0.619 to -0.364, P ​< ​0.05). Real-time PCR and Western blotting results showed that p53 was upregulated (95%CI: -3.088 to -1.912, P ​< ​0.001) and CDK1 was significantly downregulated after aspirin exposure in colon cancer cells (95% CI: 0.576 to 1.045, P ​< ​0.05). We observed that aspirin promoted G1/S cell cycle arrest in HT29 ​cells. We confirmed that aspirin induces apoptosis in human HT29 colon cancer cells in a concentration-dependent manner.

Conclusions

These results indicate that aspirin induces G1 arrest and apoptosis in colorectal cancer cells via the p53–CDK1 pathway. Aspirin may be a promising drug candidate for colon cancer prevention.

Background

Metastatic triple-negative breast cancer (mTNBC) is an aggressive histological subtype with poor prognosis. Several first-line treatments are currently available for mTNBC. This study conducted a network meta-analysis to compare these first-line regimens and to determine the regimen with the best efficacy.

Methods

A systematic search of PubMed, EMBASE, the Cochrane Central Register of Controlled Bases, and minutes of major conferences was performed. Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were analyzed via network meta-analysis using the R software (R Core Team, Vienna, Austria). The efficacy of the treatment regimens was compared using hazard ratios and 95% confidence intervals.

Results

A total of 29 randomized controlled trials involving 4607 patients were analyzed. The ranking was based on the surface under the cumulative ranking curve. Network meta-analysis results showed that cisplatin combined with nab-paclitaxel or paclitaxel was superior to docetaxel plus capecitabine in terms of PFS and ORR. For programmed death-ligand 1 (PD-L1) and breast cancer susceptibility gene (BRCA) mutation-positive tumors, atezolizumab/pembrolizumab combined with nab-paclitaxel and talazoparib was superior to docetaxel plus capecitabine. No significant difference was observed among the treatments in OS. Neutropenia, diarrhea, and fatigue were common serious adverse events.

Conclusion

Cisplatin combined with nab-paclitaxel or paclitaxel is the preferred first-line treatment for mTNBC. For PD-L1 and BRCA mutation-positive tumors, atezolizumab/pembrolizumab combined with nab-paclitaxel and talazoparib is an effective treatment option. Neutropenia, diarrhea, and fatigue are frequently occurring serious adverse events.

The significance of the heme-metabolizing enzyme heme oxygenase-1 (HMOX1) in the pathogenesis of colorectal cancer (CRC) has not been fully explored. HMOX1 cytoprotection is imperative to limit oxidative stress. However, its roles in preventing carcinogenesis in response to high levels of heme are not thoroughly understood. This study reviews various mechanisms associated with the paradoxical role of HMOX1, which is advantageous for tumor growth, refractoriness, and survival of cancer cells amid oxidative stress in heme-induced CRC. The alternate role of HMOX1 promotes cell proliferation and metastasis through immune modulation and angiogenesis. Inhibiting HMOX1 has been found to reverse tumor promotion. Thus, HMOX1 acts as a conditional tumor promoter in CRC pathogenesis.

Ferroptosis, a distinctive form of programmed cell death, is involved in numerous diseases with specific characteristics, including certain cell morphology, functions, biochemistry, and genetics, that differ from other forms of programmed cell death, such as apoptosis. Many studies have explored ferroptosis and its associated mechanisms, drugs, and clinical applications in diseases such as kidney injury, stroke, ischemia-reperfusion injury, and prostate cancer. In this review, we summarize the regulatory mechanisms of some ferroptosis inducers, such as enzalutamide and erastin. These are current research focuses and have already been studied extensively. In summary, this review focuses on the use of ferroptosis induction as a therapeutic strategy for treating tumors of the urinary system.

Immunoglobulin (Ig) isotype switching in multiple myeloma (MM) is a rare form of clonal evolution. The aim of this study was to investigate the clinical features and prognostic significance of Ig isotype switching by observing Ig transformation in patients with relapse. A retrospective analysis was performed on 506 patients with newly diagnosed MM who were treated at our hospital from February 2005 to February 2020. The patients who experienced relapse were divided into the following four groups according to Ig phenotype: original paraprotein, complete isotype switching, light chain escape (LCE),and non-secretory clinical relapse. For comparative purposes with the original paraprotein group, the last three groups were pooled as the transformation group. Among the 506 included patients, 376 (74.3%) relapsed. Among them, 13/376 (3.5%) patients exhibited Ig isotype switching, including 3 with complete isotype switching, 3 with LCE, and 7 with non-secretory clinical relapse. Eleven remained sensitive to therapy, exhibiting at least a partial response. Seven patients survived for at least 20 months after relapse. The median overall survival time of the LCE, clinical relapse, and complete isotype switching groups were 6, 20, and 76 months, respectively, after recurrence. The clinical manifestations and Ig phenotypes of MM recurrence were different from those at the initial diagnosis in the 13 patients exhibiting Ig isotype switching. These differences vividly conveyed the heterogeneity of the clonal populations and provides direct clinical evidence for MM clonal evolution.

Hairy cell leukemia (HCL) is a rare B-cell lymphoproliferative disorder. Patients typically present with cytopenia and splenomegaly. We describe the case of a 78-year-old patient with refractory HCL who acutely developed a cystic lesion on the back while receiving moxetumomab pasudotox therapy. Biopsy of the lesion revealed the presence of adenocarcinoma, which prompted a detailed evaluation resulting in a diagnosis of stage IV gastric cancer. Nevertheless, to establish any association between moxetumomab pasudotox therapy and secondary cancer development, a satisfactory number of studies need to be conducted.

Carrimycin is a synthetic macrolide antibiotic that has been shown to have anti-cancer activity; however, its exact mechanism of action and molecular target were previously unknown. It was recently elucidated that Isovalerylspiramycin I (ISP I), the active component of carrimycin, targets selenoprotein H (SelH), a nucleolar reactive oxygen species-scavenging enzyme in the selenoprotein family. ISP I treatment accelerates SelH degradation, resulting in oxidative stress, disrupted ribosomal biogenesis, and apoptosis in tumor cells. Specifically, ISP I disrupts the association between RNA polymerase I and ribosomal DNA in the nucleolus. This inhibits ribosomal RNA transcription and subsequent ribosomal assembly, which prevents cancer cells from sustaining elevated rates of protein synthesis and cellular proliferation that are necessary for tumor growth and malignancy. In this review, we (1) describe the historical categorization and evolution of anti-cancer agents, including macrolide antibiotics, (2) outline the discovery of SelH as a target of ISP I, and (3) summarize the ways in which carrimycin has been used both clinically and at the bench to date and propose additional potential therapeutic uses.

Immunotherapies boosting the immune system's ability to target cancer cells are promising for the treatment of various tumor types, yet clinical responses differ among patients and cancers. Recently, there has been increasing interest in novel cancer immunotherapy practices aimed at triggering T cell-mediated anti-tumor responses. Antigen-directed cytotoxicity mediated by T lymphocytes has become a central focal point in the battle against cancer utilizing the immune system. The molecular and cellular mechanisms involved in the actions of T lymphocytes have directed new therapeutic approaches in cancer immunotherapy, including checkpoint blockade, adoptive and chimeric antigen receptor (CAR) T cell therapy, and cancer vaccinology. This review addresses all the strategies targeting tumor pathogenesis, including metabolic pathways, to evaluate the clinical significance of current and future immunotherapies for patients with cancer, which are further engaged in T cell activation, differentiation, and response against tumors.

Background

Colorectal cancer (CRC) is the third most common malignancy and the second deadliest cancer worldwide. Metastasis to the liver, the most common metastatic site in CRC, is the leading cause of death in patients with CRC. Hyperlipidemia, which is common in patients with CRC, promotes CRC progression and metastasis. Hyperlipidemia is commonly observed in obese patients and is often induced by hypernutrition. The underlying mechanism of hypernutrition-induced hyperlipidemia in promoting CRC liver metastasis remains unclear, and there is an unmet need for effective and low-cost treatments for patients with CRC.

Methods

A mouse cecum orthotopic CRC model combined with high-fat diet (HFD) feeding, was established to mimic liver metastasis in CRC in obese patients. The effects of Dachaihu decoction (DCHD), a traditional herbal medicine used to treat inflammation and nonalcoholic fatty liver disease, and of the conventional prescription medicine obeticholic acid (OCA) were evaluated. HFD-induced obesity, hyperlipidemia, and CRC liver metastasis were assessed, along with the histology and pathology of the liver and intestine and the expression of metabolic genes in these tissues. The effects of DCHD and OCA on HFD-induced outcomes were evaluated, and human umbilical vein endothelial cells (HUVECs) treated with bile acids (BAs) and DCHD were used to study the underlying mechanisms in vitro.

Results

HFD-mediated obesity and hyperlipidemia promoted CRC metastasis, accompanied by disruption of the gut vascular barrier (GVB) and altered bile acid (BA) metabolism. DCHD decreased HFD-induced hyperlipidemia and liver metastasis in CRC, improving overall survival. Those effects of DCHD were equivalent to or better than those of OCA. DCHD regulated the expression of genes of BA metabolism and tight junctions (TJ) to prevent HFD-induced disruption of the GVB. In HUVECs, DCHD prevented the increases in intracellular Ca²⁺ and accumulation of reactive oxygen species induced by primary conjugated BAs, assisting in the maintenance of redox homeostasis and preventing the downregulation of TJ proteins, thereby maintaining the integrity of the endothelial barrier.

Conclusions

The data provide a link between hypernutrition and GVB disruption, which contributes to high liver metastasis in patients with CRC. DCHD may represent a novel therapy in CRC, and targeting abnormal lipid metabolism could be a promising therapeutic strategy for avoiding hypernutrition-associated CRC metastasis.