Abstract Objectives Our present study has shown a potential role for VEGF‐A‐mediated autocrine signalling to promote survival and proliferation of SU‐DHL‐6 cells, but the cells could not undergo apoptosis but rather decrease proliferation after bevacizumab treatment. Therefore, we would like to further study the antitumour efficacy of venetoclax (BCL2 inhibitor) in combination with bevacizumab in B‐cell NHL. Methods The human cytokine antibody array, RT‐qPCR, Western blot, ELISA, apoptosis assay and xenografted mouse model et al were used. Results We described a unique phenomenon that SU‐DHL‐6 cells showed cell density‐dependent survival and growth. Then, we suggested the expression of VEGF‐A was positively correlated with the cell density using a human cytokine antibody array and indicated an important role of VEGF‐A in the survival and proliferation of SU‐DHL‐6 cells. Additionally, xenografted SU‐DHL‐6 cells formed tumours in mice that grew in response to VEGF stimulation. GEO data set also suggested that high VEGF‐A expression reflected poor prognosis. The combination therapy with bevacizumab and navitoclax could significantly induce of cell death in vitro and reduce the tumour size and weight with well tolerated in vivo. Conclusions Our findings propose a novel combined strategy in which bevacizumab synergises with the BCL2 inhibitor venetoclax that is effective against B‐cell NHL.
Most cancer-related deaths result from the progressive growth of metastases. Patients with peritoneal metastatic (PM) colorectal cancer have reduced overall survival. Currently, it is still unclear why colorectal cancer (CRC) cells home to and proliferate inside the peritoneal cavity, and there is no effective consolidation therapy for improved survival. Using a proteomic approach, we found that key enzymes of fatty acid oxidation (FAO) were decreased in patients with PM colorectal cancer. Furthermore, we confirmed that carnitine palmitoyltransferase IA (CPT1A), a rate-limiting enzyme of FAO, was expressed at significantly low levels in patients with PM colorectal cancer, as determined by RT-qPCR, IHC, and GEO dataset analysis. However, lipidomics revealed no difference in FFA levels between PM and non-PM primary tumors. Here, we showed that cancer-associated fibroblasts (CAFs) promote the proliferation, migration, and invasion of colon cancer cells via upregulating CPT1A to actively oxidize FAs and conduct minimal glycolysis. In addition, coculture-induced glycolysis increased in cancer cells while fatty acid catabolism decreased with lower adiponectin levels. Importantly, inhibition of glycolysis significantly reduced the survival of CRC cells after incubation with conditioned medium from CAFsCPT1A-OE in vitro and impaired the survival and growth of organoids derived from CRC-PM. Finally, we found that directly blocking FAO in CAFsCPT1A-OE with etomoxir inhibits migration and invasion in vitro and decreases tumor growth and intraperitoneal dissemination in vivo, revealing a role for CAF CPT1A in promoting tumor growth and invasion. In conclusion, our results suggest the possibility of testing FAO inhibition as a novel approach and clinical strategy against CAF-induced colorectal cancer with peritoneal dissemination/metastases.
Laparoscopic adjustable gastric banding (LAGB) and laparoscopic sleeve gastrectomy (LSG) are common weight loss procedures. Our meta-analysis compared these procedures for the treatment of morbid obesity and related diseases.We systematically searched the PubMed, Embase, and the Cochrane Library through January 2018. The percentage of excess weight loss (%EWL), improvement or remission of type 2 diabetes mellitus (T2DM) and hypertension were analyzed and compared.Thirty-three studies with 4109 patients were included. Greater decreases in excess weight were found in patients who received LSG at 6 months (weighted mean difference (WMD) -9.29, 95% confidence interval (CI): -15.19 to -3.40, P = .002), 12 months (WMD -16.67 95% CI: -24.30 to -9.05, P < .0001), 24 months (WMD -19.63, 95% CI: -29.00 to -10.26, P < .0001), and 36 months (WMD -19.28, 95% CI: -27.09 to -11.47, P < .0001) than in patients who received LAGB. However, there were no significant differences in the 3-month outcomes between the 2 groups (WMD -1.61, 95% CI: -9.96 to 6.73, P = .70). T2DM patients after LSG experience more significant improvement or remission of diabetes (odds ratio (OR): 0.22, 95% CI: 0.06-0.87, P = .03). The 2 groups did not significantly differ regarding improvement or remission of hypertension (OR 0.80, 95% CI: 0.46-1.38, P = .42).LSG is a more effective procedure than LAGB for morbidly obese patients, contributing to a higher %EWL and greater improvement in T2DM.
In recent decades, neoadjuvant therapy (NT) has been the standardized treatment for locally advanced rectal cancer (LARC). Approximately 8%-35% of patients with LARC who received NT were reported to have achieved a complete pathological response (pCR). If the pathological response (PR) can be accurately predicted, these patients may not need surgery. In addition, no response after NT implies that the tumor is destructive, resistant to both chemotherapy and radiotherapy, and prone to having a high metastatic potential. Therefore, developing accurate models to predict PR has great clinical significance and can help achieve individualized treatment in LARC patients.To establish nomograms for predicting PR to different NT regimens based on pretreatment parameters for patients with LARC.Rectal cancer patients were identified from the database of The Sixth Affiliated Hospital, Sun Yat-sen University from January 2012 to December 2016. Logistic regression and nomograms were developed to predict the probability of pCR and good downstaging to ypT0-2N0M0 (ypTNM 0-I), respectively, based on pretreatment parameters for all LARC patients. Nomograms were also developed for three NT regimens (capecitabine/deGramont-RT, mFOLFOX6, and mFOLFOX6-RT) to predict pCR probability.Four hundred and three patients were included in this study; 72 (17.9%) had pCR at the final pathology report, and 177 (43.9%) achieved good downstaging to ypT0-2N0M0 (ypTNM 0-I). The nomogram for predicting pCR probability showed that NT regimens, tumor differentiation, mesorectal fascia (MRF) status, and tumor length significantly influenced pCR probability. When predicting the probability of good downstaging, tumor differentiation, MRF status, and clinical T stage were the significant factors. Nomograms were developed based on NT regimens. For the capecitabine/de Gramont-RT group, the multivariate analysis showed that the neutrophil-lymphocyte ratio (NLR) was the only significant factor, thus we could not develop a nomogram for this regimen. For the mFOLFOX6-RT group, the analysis showed that the significant factors were tumor length and MRF status; and for the mFOLFOX6 group, the significant factors were tumor length and tumor differentiation.We established accurate nomograms for predicting the PR to preoperative NT regimens based on pretreatment parameters for LARC patients.
<div>Abstract<p>DNA methylation contributes to malignant transformation, but little is known about how the methylation drives colorectal cancer evolution at the early stages. Here we identify aberrant INA (α-internexin) gene methylation in colon adenoma and adenocarcinoma by filtering data obtained from a genome-wide screen of methylated genes. The gene encoding INA, a type IV intermediate filament, was frequently hypermethylated in CpG islands located in the promoter region. This hypermethylation preferentially occurred in large tumors and was a prognostic marker for poor overall survival in patients with colorectal cancer. This type of epigenetic alteration silenced INA expression in both adenoma and adenocarcinoma tissues. Gene silencing of INA in colorectal cancer cells increased cell proliferation, migration, and invasion. Restored INA expression blocked migration and invasion <i>in vitro</i> and reduced lung metastasis <i>in vivo</i>. Mechanistically, INA directly inhibited microtubule polymerization <i>in vitro</i> and decreased intracellular microtubule plus-end assembly rates. A peptide array screen surveying the tubulin-binding sites in INA identified a tubulin-binding motif located in the N-terminal head domain that plays a tumor-suppressive role by binding to unpolymerized tubulins and impeding microtubule polymerization. Thus, epigenetic inactivation of INA is an intermediate filament reorganization event that is essential to accelerate microtubule polymerization in the early stages of colorectal cancer.</p>Significance:<p>This work provides insight into the epigenetic inactivation of INA, a novel identified tumor suppressor, which increases microtubule polymerization during colorectal cancer progression.</p></div>
Background Colony-stimulating factor 1 receptor (CSF1R), a classic tyrosine kinase receptor, has been identified as a proto-oncogene in multiple cancers. The CSF1/CSF1R axis is essential for the survival and differentiation of M2-phenotype tumor-associated macrophages (M2 TAMs). However, we found here that the CSF1R expression was abnormally down-regulated in colorectal cancer (CRC), and its biological functions and underlying mechanisms have become elusive in CRC progression. Methods The expression of class III receptor tyrosine kinases in CRC and normal intestinal mucosa was accessed using The Cancer Genome Atlas and Gene Expression Omnibus datasets and was further validated by our tested cohort. CSF1R was reconstructed in CRC cells to identify its biological functions in vitro and in vivo . We compared CSF1R expression and methylation differences between CRC cells and macrophages. Furthermore, a co-culture system was used to mimic a competitive mechanism between CSF1R-overexpressed CRC cells and M2-like macrophages. We utilized a CSF1R inhibitor PLX3397 to ablate M2 TAMs and evaluated its efficacy on CRC treatment in animal models. Results We found here that the CSF1R is silenced in CRC, and the reintroduced expression of the receptor in CRC cells can be cleaved by caspases and constrain tumor growth in vitro and in vivo , functioning as a tumor suppressor gene. We further identified CSF1R as a novel dependence receptor, which has the potential to act as either a tumor suppressor gene or an oncogene, depending on its activated state. In CRC tumors, CSF1R expression is enriched in TAMs, and its expression is associated with poor prognosis in patients ith CRC. In a co-culture system, CRC cells expressing CSF1R compete with M2-like macrophages for CSF1R ligands, resulting in a decrease in CSF1R activation and cell proliferation in macrophages. Blocking CSF1R by PLX3397 could deplete M2 TAMs and augments CD8 + T cell infiltration, effectively inhibiting tumor growth and metastasis and improving responses to chemotherapy and immunotherapy. Conclusion Our findings revealed that CSF1R is a novel identified dependence receptor silenced in CRC. The silence abalienates its ligands to stimulate CSF1R expressed on M2 TAMs, which is an appealing therapeutic target for M2 TAM depletion and CRC treatment.
Objective: To investigate the risk factors associated with intrahepatic recurrence and survival after microwave ablation (MWA) for colorectal cancer with liver metastases. Methods: Retrospective analysis of clinical, pathological and follow-up data of 60 patients who underwent ultrasound-guided microwave ablation for treating liver metastases from January 2013 to December 2015 at the Sixth Affiliated Hospital, Sun Yat-Sen University, with Cox univariate and multifactorial regression analyses of risk factors affecting intrahepatic recurrence and overall survival after ablation of liver metastases. Results: After follow-up for 12.5 to 47.4 months, intrahepatic recurrence occurred in 26 cases, of which 6.1% (7/114) showed local tumor progression at the original ablation site; 11 cases died for tumor-related reasons. Multi-factor Cox regression analysis showed that age ≥60 years and maximum diameter of liver metastases ≥2 cm were independent risk factors for patients to develop intrahepatic recurrence after surgery. HBsAb positivity and chemotherapy after ablation until intrahepatic recurrence are independent protective factors for patients developing intrahepatic recurrence after surgery. Multi-factor Cox regression analysis showed that the number of liver metastases ≥3 was an independent risk factor for overall survival. Conclusion: After microwave ablation for patients with colorectal cancer liver metastases, patients aged ≥60 years, HBsAb negative and with maximum liver metastases ≥2 cm in diameter were more likely to have recurrent intrahepatic metastases, while aggressive chemotherapy after ablation was effective in reducing recurrent intrahepatic metastases, and the number of liver metastases ≥3 indicated a poor overall prognosis.
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