In recent years, in-depth studies have shown that extracellular matrix stiffness plays an important role in cell growth, proliferation, migration, immunity, malignant transformation, and apoptosis. Most of these processes entail metabolic reprogramming of cells. However, the exact mechanism through which extracellular matrix stiffness leads to metabolic reprogramming remains unclear. Insights regarding the relationship between extracellular matrix stiffness and metabolism could help unravel novel therapeutic targets and guide development of clinical approaches against a myriad of diseases. This review provides an overview of different pathways of extracellular matrix stiffness involved in regulating glucose, lipid and amino acid metabolism.

Previous studies reported that Follistatin-like 3 (FSTL3) is abundantly expressed in several solid tumors and participate in the regulation of cell metabolism. However, the clinico-pathological significance, biological role and molecular mechanism of FSTL3 in colorectal cancer (CRC) is still unclear. Here we report that the expression level of FSTL3 in colon cancer specimens was significantly higher, compared to normal tissue and interestingly, the expression of FSTL3 was related to lymph node metastasis, tumor stage, tumor size, and intravascular emboli (IVE). As an upstream molecular event, we found that transcriptional regulation of FSTL3 was highly dependent on YAP1 de-phosphorylation events and that increased FSTL3 expression readily activated the β-Catenin pathway, which is a well-known signaling hub that promotes EMT processes and aerobic glycolysis in cancer cells. We found that elevated FSTL3 expression strongly promotes migration, invasion and metastatic formation of CRC cells by directly activating β-Catenin -mediated EMT and aerobic glycolysis. In the xenograft mouse model, FSTL3 expression was linked to increased metastatic formation of CRC cells. Together, the activation of YAP1 induces FSTL3 expression. FSTL3-mediated β-Catenin pathway activation promotes EMT and aerobic glycolysis and therefore affecting the invasive and metastatic capacity of CRC cells. The abundant FSTL3 expression is a poor prognostic factor and pharmacological targeting of YAP1 can counteract FSTL3 expression, suggesting a promising therapeutic target for anti-metastatic strategies in patients suffering from CRC.

N6-methyladenosine (m6A) modifications of RNAs are involved in various aspects of colorectal carcinogenesis via regulation of mRNA stability, splicing, and translation. KIAA1429, an m6A methyltransferase, was found deregulated in multiple cancer types. However, its role in colorectal cancer remains elusive. By analyzing TCGA and GEPIA database, we found that KIAA1429 in colorectal cancer was highly expressed. In addition, we used immunohistochemistry, western blotting, and QRT-PCR to detect the expression of KIAA1429 in colorectal cancer samples and cell lines, and we found that KIAA1429 was overexpressed in colorectal cancer sample and cell line. Functionally, silencing of KIAA1429 by shRNA in colorectal cancer cell lines resulted in decreased cell proliferation, colony formation, and migration. On the contrary, overexpression of KIAA1429 increased cell proliferation, colony formation, and migration. Further mechanism analysis demonstrated that KIAA1429 increased the expression of SIRT1 via regulating its mRNA stability in an m6A-dependent manner. More importantly, in vivo experiment showed that depletion of KIAA1429 significantly inhibited colorectal tumor growth. In conclusion, our results suggested that the m6A methyltransferase KIAA1429 promotes the growth and motility of colorectal cancer and could be a potent therapeutic target.

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Objective Despite controversy over its origin and definition, the significance of tumour deposit (TD) has been underestimated in the tumour node metastasis (TNM) staging system for colon cancer, especially in stage III patients. We aimed to further confirm the prognostic value of TD in stage III colon cancer and to establish a more accurate ‘coN’ staging system combining TD and lymph node metastasis (LNM). Methods Information on stage III colon cancer patients with a definite TD status was retrospectively collected from the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2017. The effect of TD on prognosis was estimated using Cox regression analysis. Maximally selected rank statistics were used to select the optimal cut‐off value of TD counts. The predictive power of conventional N staging and the new coN staging was evaluated and compared by Akaike's information criterion (AIC), Harrell's concordance index (C‐index) and time‐dependent receiver operating characteristic (ROC) curves. Clinicopathological data of stage III colon cancer patients in the Xiangya database from 2014 to 2018 were collected to validate the coN staging system. Results A total of 39,185 patients with stage III colon cancer were included in our study: 38,446 in the SEER cohort and 739 in the Xiangya cohort. The incidence of TD in stage III colon cancer was approximately 30% (26% in SEER and 30% in the Xiangya database). TD was significantly associated with poorer overall survival (OS) (HR = 1.37, 95% CI 1.31–1.44, p < 0.001 in SEER). The optimal cut‐off value of TD counts was 4, and the patients were classified into the TD0 (count = 0), TD1 (count = 1–3) and TD2 (count ≥ 4) groups accordingly. The estimated 5‐year OS was significantly different among the three groups (69.4%, 95% CI 68.8%–70.0% in TD0; 60.5%, 95% CI 58.9%–62.2% in TD1 and 42.6%, 95% CI 39.2%–46.4% in TD2, respectively, p < 0.001). The coN system integrating LNM and TD was established, and patients with stage III colon cancer were reclassified into five subgroups (coN1a, coN1b, coN2a, coN2b and coN2c). Compared with conventional N staging, the coN staging Cox model had a smaller AIC (197097.581 vs. 197358.006) and a larger C‐index (0.611 vs. 0.601). The AUCs of coN staging at 3, 5 and 7 years were also greater than those of conventional N staging (0.6305, 0.6326, 0.6314 vs. 0.6186, 0.6197, 0.6160). Concomitant with the SEER cohort results, the coN staging Cox model of the Xiangya cohort also had a smaller AIC (2883.856 vs. 2906.741) and a larger C‐index (0.669 vs. 0.633). Greater AUCs at 3, 5 and 7 years for coN staging were also observed in the Xiangya cohort (0.6983, 0.6774, 0.6502 vs. 0.6512, 0.6368, 0.6199). Conclusions Not only the presence but also the number of TDs is associated with poor prognosis in stage III colon cancer. A combined N staging system integrating LNM...

Objective To analyze the effect of neoadjuvant radiotherapy (nRT) on prognosis in patients with locoregional Siewert type II gastroesophageal junction adenocarcinoma (GEA). Method All patients pathologically diagnosed as Siewert type II GEA between 2004 and 2015 were retrieved from the Surveillance, Epidemiology and Final Results (SEER) database. We analyzed the impact of different treatment regimens on the prognosis in each stage. Survival analysis was performed by Kaplan-Meier (K-M) method. Multivariate Cox model and propensity score matching was further used to verify the results. Results 4,160 patients were included in this study. The efficacy of nRT was superior to that of adjuvant radiotherapy (aRT) (p = 0.048), which was the same as that of surgery combined with chemotherapy (p = 0.836), but inferior to the overall survival (OS) of surgical treatment alone (p<0.001) in T1-2N0M0 patients. Patients receiving nRT had distinctly better survival than those receiving surgical treatment alone (p = 0.008), but had similar survival compared with patients treated with aRT (p = 0.989) or surgery combined with chemotherapy (p = 0.205) in the T3N0/T1-3N+M0 subgroup. The efficacy of nRT is clearly stronger than that of surgical therapy alone (p<0.001), surgery combined with chemotherapy (p<0.001), and aRT (p = 0.008) in patients with T4 stage. The survival analysis results were consistent before and after propensity score matching. Conclusion In these carefully selected patients, the present study made the following recommendations: nRT can improve the prognosis of patients with T3N0M0/T1-3N+M0 and T4 Siewert type II GEA, and it seems to be a better treatment for T4 patients. Surgery alone seems to be sufficient, and nRT is not conducive to prolonging the survival of Siewert II GEA patients with T1-2N0M0 stage. Of course, further prospective trials are needed to verify this conclusion.

Background: Chemotherapy is suggested to use in all stages of pancreatic cancer. Is it reasonable to recommend chemotherapy for all PDAC patients? It is necessary to distinguish low-risk PDAC patients underwent pancreatectomy, who may not lose survival time due to missed chemotherapy and not need to endure pain, nausea, tiredness, drowsiness, and breath shortness caused by chemotherapy. Methods: Nomograms were constructed with basis from the multivariate Cox regression analysis. X-tile software was utilized to perform risk stratification. Survival curves were used to display the effect of chemotherapy in different risk-stratification. Results: All of the significant variables were used to create the nomograms for overall survival (OS). The total risk score of each patient was calculated by summing the scores related to each variable. X-tile software was utilized to classify patients into high-risk (score >283), median-risk (197

BackgroundIt remains controversial whether radiotherapy (RT) improves survival in patients with stage IIB/III PDAC. A growing number of studies have found that patients’ age at diagnosis and tumor site not only affect prognosis, but also may lead to different treatment responses. Therefore, the purpose of this study was to verify whether the survival effect of radiotherapy in patients with stage IIB/III PDAC varies across age and tumor site groups.MethodsThe target population was selected from PDAC patients undergone surgery in the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2016. This study performed the Pearson’s chi-square test, Cox regression analysis, Kaplan-Meier (K-M) method, and focused on propensity frequency matching analysis.ResultsNeither neoadjuvant radiotherapy (nRT) nor adjuvant radiotherapy (aRT) patient group had probably improved survival among early-onset patients. For middle-aged patients, nRT seemed to fail to extend overall survival (OS), while aRT might improve the OS. Plus, both nRT and aRT were associated with improved survival in elderly patients. The aRT might be related with survival benefits in patients with pancreatic head cancer, while nRT was not. And RT in patients with PDAC at other sites did not appear to provide a survival benefit.ConclusionCarefully selected data from the SEER database suggested that age and tumor location may be the reference factors to guide the selection of RT for patients with stage IIB/III PDAC. These findings are likely to contribute to the development of personalized treatment for patients with stage IIB/III PDAC.