Neoadjuvant Chemotherapy With Oxaliplatin and Fluoropyrimidine Versus Upfront Surgery for Locally Advanced Colon Cancer: The Randomized, Phase III OPTICAL Trial.

PURPOSE: The role of neoadjuvant chemotherapy (NAC) in colon cancer remains unclear. This trial investigated whether 3 months of modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine and oxaliplatin (CAPOX) as NAC could improve outcomes in patients with locally advanced colon cancer versus upfront surgery. PATIENTS AND METHODS: OPTICAL was a randomized, phase III trial in patients with clinically staged locally advanced colon cancer (T3 with extramural spread into the mesocolic fat ≥5 mm or T4). Patients were randomly assigned 1:1 to receive six preoperative cycles of mFOLFOX6 or four cycles of CAPOX, followed by surgery and adjuvant chemotherapy (NAC group), or immediate surgery and the physician's choice of adjuvant chemotherapy (upfront surgery group). The primary end point was 3-year disease-free survival (DFS) assessed in the modified intention-to-treat (mITT) population. RESULTS: Between January 2016 and April 2021, of the 752 patients enrolled, 744 patients were included in the mITT analysis (371 in the NAC group; 373 in the upfront surgery group). At a median follow-up of 48.0 months (IQR, 46.0-50.1), 3-year DFS rates were 82.1% in the NAC group and 77.5% in the upfront surgery group (stratified hazard ratio [HR], 0.74 [95% CI, 0.54 to 1.03]). The R0 resection was achieved in 98% of patients who underwent surgery in both groups. Compared with upfront surgery, NAC resulted in a 7% pathologic complete response rate (pCR), significantly lower rates of advanced tumor staging (pT3-4: 77% v 94%), lymph node metastasis (pN1-2: 31% v 46%), and potentially improved overall survival (stratified HR, 0.44 [95% CI, 0.25 to 0.77]). CONCLUSION: NAC with mFOLFOX6 or CAPOX did not show a significant DFS benefit. However, this neoadjuvant approach was safe, resulted in substantial pathologic downstaging, and appears to be a viable therapeutic option for locally advanced colon cancer.

Comprehensive survival nomograms for locally advanced gastric cancer: a large population-based real-world study.

Background: This study aimed to construct and verify nomograms predicting overall survival (OS) and cancer-specific survival (CSS) for locally advanced gastric cancer (LAGC) based on a therapeutic selection, demographic factors, and pathological features. Methods: The data used for the analysis were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Nomograms were constructed based on the Cox regression model. Results: The entire cohort comprised 21,757 patients with histologically confirmed LAGC, and was randomly distributed into training and verification groups at a ratio of 2:1 for building the prognostic predictive model. According to the multivariate analysis, 13 variables [i.e., age, marital status, race, tumor location, pathological grade, histological type, T and N stage, surgery, radiotherapy, chemotherapy, tumor size, and regional nodes examined (RNE)] were confirmed as independent predictors for both OS and CSS. All of the significant variables were used to create the nomograms for OS and CSS. Time-dependent receiver operating characteristic (ROC) curves, a decision curve analysis (DCA), the C-index, and calibration curves were applied to identify the discriminating superiority of the nomograms. Conclusions: The nomograms for OS and CSS in LAGC were built and validated based on the therapeutic selection and pathological and demographic variables using a national database. This study aims at helping clinicians make better clinical decisions and encouraging patients receive treatment actively.

Phosphorylation of PPDPF via IL6-JAK2 activates the Wnt/ß-catenin pathway in colorectal cancer.

Inflammation plays an important role in the initiation and progression of colorectal cancer (CRC) and leads to ß-catenin accumulation in colitis-related CRC. However, the mechanism remains largely unknown. Here, pancreatic progenitor cell differentiation and proliferation factor (PPDPF) is found to be upregulated in CRC and significantly correlated with tumor-node-metastasis (TNM) stages and survival time. Knockout of PPDPF in the intestinal epithelium shortens crypts, decreases the number of stem cells, and inhibits the growth of organoids and the occurrence of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CRC. Mechanistically, PPDPF is found to interact with Casein kinase 1α (CK1α), thereby disrupting its binding to Axin, disassociating the ß-catenin destruction complex, decreasing the phosphorylation of ß-catenin, and activating the Wnt/ß-catenin pathway. Furthermore, interleukin 6 (IL6)/Janus kinase 2 (JAK2)-mediated inflammatory signals lead to phosphorylation of PPDPF at Tyr16 and Tyr17, stabilizing the protein. In summary, this study demonstrates that PPDPF is a key molecule in CRC carcinogenesis and progression that connects inflammatory signals to the Wnt/ß-catenin signaling pathway, providing a potential novel therapeutic target.

The new 'coN' staging system combining lymph node metastasis and tumour deposit provides a more accurate prognosis for TNM stage III colon cancer.

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 and TD provides more accurate prognostic prediction than the latest AJCC N staging in stage III colon cancer.

The Association of R-Loop Binding Proteins Subtypes with CIN Implicates Therapeutic Strategies in Colorectal Cancer.

Chromosomal instability (CIN) covers approximately 65 to 70% of colorectal cancer patients and plays an essential role in cancer progression. However, the molecular features and therapeutic strategies related to those patients are still controversial. R-loop binding proteins (RLBPs) exert significant roles in transcription and replication. Here, integrative colorectal cancer proteogenomic analysis identified two RLBPs subtypes correlated with distinct prognoses. Cluster I (CI), represented by high expression of RLBPs, was associated with the CIN phenotype. While Cluster II (CII) with the worst prognosis and low expression of RLBPs was composed of a high percentage of patients with mucinous adenocarcinoma or right-sided colon cancer. The molecular feature analysis revealed that the active RNA processing, ribosome synthesis, and aberrant DNA damage repair were shown in CI, a high inflammatory signaling pathway, and lymphocyte infiltration was enriched in CII. In addition, we revealed 42 tumor-associated RLBPs proteins. The CI with high expression of tumor-associated proteins was sensitive to drugs targeting genome integrity and EGFR in both cell and organoid models. Thus, our study unveils a significant molecular association of the CIN phenotype with RLBPs, and also provides a powerful resource for further functional exploration of RLBPs in cancer progression and therapeutic application.

m6A Methyltransferase KIAA1429 Regulates the Cisplatin Sensitivity of Gastric Cancer Cells via Stabilizing FOXM1 mRNA.

Although cisplatin is frequently used to treat gastric cancer, the resistance is the main obstacle for effective treatment. mRNA modification, N6-methyladenosine (m6A), is involved in the tumorigenesis of many types of cancer. As one of the largest m6A methyltransferase complex components, KIAA1429 bridges the catalytic m6A methyltransferase components, such as METTL3. In gastric cancer, KIAA1429 was reported to promote cell proliferation. However, whether KIAA1429 is involved in the resistance of gastric cancer to cisplatin remains unclear. Here, we generated cisplatin resistant gastric cancer cell lines, and compared the m6A content between resistant cells and wild type cells. The m6A content as well as KIAA1429 expression are higher in resistant cells. Interestingly, the expression of KIAA1429 was significantly increased after cisplatin treatment. We then used shRNA to knockdown KIAA1429 and found that resistant cells responded more to cisplatin treatment after KIAA1429 depletion, while overexpression of KIAA1429 decreased the sensitivity. Moreover, we identified a putative p65 binding site on the promoter area of KIAA1429 and ChIP assay confirmed the binding. p65 depletion decreased the expression of KIAA1429. YTHDF1 is the most abundant m6A "reader" that interacts with m6A modified mRNA. Mechanistically, YTHDF1 was recruited to the 3'-untranslated Region (3'-UTR) of transcriptional factor, FOXM1 by KIAA1429 and stabilized FOXM1 mRNA. More importantly, KIAA1429 knockdown increased the sensitivity of resistant cells to cisplatin in vivo. In conclusion, our results demonstrated that KIAA1429 facilitated cisplatin resistance by stabilizing FOXM1 mRNA in gastric cancer cells.

Prognostic Value of the N1c in Stage III and IV Colorectal Cancer: A Propensity Score Matching Study Based on the Surveillance, Epidemiology, and End Results (SEER) Database.

The prognostic role of the N1c remains unclear in colorectal cancer (CRC). Our study aimed to determine the prognostic value of N1c.Patients diagnosed in 2010-2015 were accessed from the Surveillance, Epidemiology, and End Results (SEER) database. COX univariate and multivariate regression analysis and the Kaplan-Meier method were used to assess the impact of the N1c stage on the cause-specific (CSS) and overall survival (OS). Propensity score matching (PSM) was used to construct a matched group with similar propensity scores.Kaplan-Meier analysis showed that the CSS and OS rates in N1a were significantly better than N1c in stage III and IV CRCs after reducing selection bias (CSS: P < 0.001 in stage III, P = 0.041 in stage IV; OS: P < 0.001 in stage III, P = 0.0079 in stage IV). There were no statistical differences in CSS and OS between N1b and N1c (CSS: P = 0.500 in stage III, P = 0.270 in stage IV; OS: P = 0.390 in stage III, P = 0.600 in stage IV). Further, the prognostic value of N1c with only one tumor deposit (TD) is equivalent to N1a based on the comparison of CSS and OS rates (CSS: P = 0.420; OS: P = 0.310). Whereas N1c with only one TD had significantly better CSS and OS than N1b (CSS: P = 0.039; OS: P = 0.037).The CSS and OS rates of N1c do not achieve a statistical difference with N1b in both stage III and IV CRCs. Significantly, higher CSS and OS rates were found in N1c with only one TD versus N1b stage in stage III CRC.

The Survival Effect of Radiotherapy on Stage II/III Rectal Cancer in Different Age Groups: Formulating Radiotherapy Decision-Making Based on Age.

INTRODUCTION: Total mesorectal excision (TME), chemotherapy (CT), and radiotherapy (RT) are usually integrated into the comprehensive treatment of stage II/III rectal cancer (RC). Neoadjuvant radiotherapy (nRT) has become the standard treatment for stage II/III RC patients to help reduce the size of a tumor or kill cancer cells that have spread. Adjuvant RT is delivered after the resection to destroy remaining cancer cells and used mainly in stage II/III RC patients who have not received preoperative radiotherapy, such as those who suffered from a bowel obstruction before surgery. It is controversial whether radiotherapy can improve the survival of stage II/III RC patients. An increasing number of studies have reported that rectal cancer exhibited mismatched biology, epidemiology, and therapeutic response to current treatment strategy in different age groups. It is necessary to investigate whether radiotherapy exhibits disparate effects in different age groups of patients with stage II/III RC. METHODS: Data from the Surveillance, Epidemiology, and End Results (SEER) Program was extracted to identify stage II/III RC diagnosed in the periods of 2004-2016. The statistical methods included Pearson's chi-square test, log-rank test, Cox regression model, and propensity score matching. RESULTS: Neoadjuvant radiotherapy (nRT) cannot improve the prognosis, and postoperative RT may even reduce the survival time for early onset stage II/III RC. Postoperative RT was not able to improve the overall survival (OS), while nRT may provide limited survival improvement for middle-aged stage II/III RC patients. In addition, radiotherapy can significantly improve the prognosis for elderly stage II/III RC. CONCLUSIONS: This study indicated the inconsistent survival effect of radiotherapy on stage II/III rectal cancer patients in different age groups. Hence, we formulated a novel flow chart of radiotherapy decision-making based on age in stage II/III RC patients.

Intravascular emboli relates to immunosuppressive tumor microenvironment and predicts prognosis in stage III colorectal cancer.

BACKGROUND: Stage III colorectal cancer (CRC) patients experience varying degrees of prognosis even if receiving standard therapeutic regimes. Intravascular emboli (IVE), a type of vascular invasion, impacts the clinical outcome in CRC. In this study, we confirmed the role of IVE in predicting the prognosis of stage III CRC patients and characterized the tumor microenvironment (TME) of CRC with IVE. METHODS: Data from 220 consecutive patients (cohort 1) with stage III CRC undergoing radical surgery was collected retrospectively between January 2009 to December 2014. According to the presence of IVE, which was confirmed by two independent pathologists, patients were classified into two groups. Univariate and multivariate Cox regression analyses were performed to evaluate the relation of IVE presence to patients' prognosis. The association between IVE and clinicopathological factors was also analyzed. Furthermore, differentially expressed genes (DEGs) and gene set enrichment analyses (GSEA) were performed to describe features of the TME based on microarray data consisting of 6 patients. Tumor tissues from a separate cohort of 73 patients with stage III CRC (cohort 2) collected between June 2014 and December 2015 were used to analyze tumor-infiltrating lymphocyte (TIL) by immunohistochemistry (IHC) staining. RESULTS: IVE was observed in 126 (57.3%) patients and could serve as an unfavorable independent prognostic predictor (P < 0.001) as well as lymph node metastasis (P < 0.05) and tumor location (P < 0.05). Additionally, patients with IVE had a higher neutrophil percentage (P = 0.002) and lower lymphocyte percentage (P = 0.002) relative to those without IVE. CRC with IVE had a significantly different profile of DEGs compared to CRC without IVE, and GSEA showed chronic inflammatory and immunosuppressive TME may promote IVE development. In cohort 2, tumors with IVE had fewer CD3+ TILs in the stromal region, as well as fewer CD8+ TILs in both stromal and tumoral regions relative to those without IVE. CONCLUSION: IVE, which was related closely to a chronic inflammatory and immunosuppressive TME, forecasted a worse prognosis of stage III CRC patients and may be taken into consideration when a therapeutic strategy is decided upon.

Has the increase in the regional nodes evaluated improved survival rates for patients with locoregional colon cancer?

Background: The guidelines for colon cancer surgery have been evolving over the past three decades. The advances in colectomy have focused mainly on the number of regional nodes evaluated (RNE). Methods: Data in this retrospective analysis were extracted from the Surveillance, Epidemiology, and End Results (SEER) linked database. Results: Rapid growth of RNE (the median rising from 10 (6-16) to 17 (13-23)) occurred from 2000 to 2009. The rate of colon cancer patients with positive lymph nodes following colectomy was greatly decreasing only in the group with RNE greater than 12 after 2000. Patients with T4 and/or N+ cannot obtain survival benefit from the increasing trend of RNE. The apparent survival benefit for T1-3N0 patients may result from augmented false negatives in patients from previous periods. Conclusions: The golden period of surgical development in colon cancer, using RNE as an alternative indicator, occurred in the first decade of the 21st century. Although a more extensive lymph node evaluation is able to reduce the risk of underestimated staging, the increase of RNE does not provide survival benefits for locoregional colon cancer. A proper reduction in the scope of lymph node dissection may be reasonable in radical surgery for colon cancer.

lncRNA SNHG4 modulates colorectal cancer cell cycle and cell proliferation through regulating miR-590-3p/CDK1 axis.

Colorectal cancer (CRC) is a prevalent malignancy worldwide. The development of genome sequencing technology has allowed the discovery that epigenetic regulation might play a critical role in CRC tumorigenesis. In the present study, we found that the long noncoding RNA (lncRNA) SNHG4 was dramatically increased in CRC tissue samples and cell lines based on both publicly available and experimental data. SNHG4 knockdown suppressed the viability and colony formation capacity of CRC cells. The expression of CDK1 was considerably increased in CRC tissue samples and cells and had a positive correlation with the expression of SNHG4 in CRC. SNHG4 silencing not only caused S phase cell cycle arrest but also significantly downregulated the CDK1, cyclin B1, and cyclin A2 protein levels in CRC cells. miR-590-3p simultaneously bound to SNHG4 and CDK1. miR-590-3p functioned to inhibit CDK1 expression. miR-590-3p overexpression exerted the same effects on the CRC cell phenotype as SNHG4 knockdown. The effects of si-SNHG4 on CRC cells were significantly reversed by anti-miR-590-3p, indicating that SNHG4 relieved the miR-590-3p-induced inhibition of CDK1 by acting as a competing endogenous RNA (ceRNA). In vivo, SNHG4 silencing inhibited subcutaneously transplanted tumor growth and decreased cell cycle marker levels, whereas miR-590-3p inhibition exerted the opposite effects. The in vivo effects of SNHG4 silencing were also reversed by miR-590-3p inhibition. The SNHG4/miR-590-3p/CDK1 axis influences the cell cycle to modulate CRC cell proliferation and subcutaneously transplanted tumor growth. Further application of this axis still requires analysis using more animal models and clinical investigations.

Extracellular Matrix Stiffness: New Areas Affecting Cell Metabolism.

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.

The Relationship between Primary Gross Tumor Volume and Tumor Response of Locally Advanced Rectal Cancer: pGTV as a More Accurate Tumor Size Indicator.

Purpose: To identify the clinical predictive factors of tumor response and to evaluate the significance of primary gross tumor volume (pGTV), obtained from radiotherapy planning, in predicting tumor response. Materials and Methods: We retrospectively analyzed data of consecutive locally advanced rectal cancer (LARC) patients who were treated with neoadjuvant chemoradiotherapy (nCRT) followed by radical surgery at our institution between March 2009 and December 2017. We identify independent predictors of tumor response to nCRT by statistical analysis. Disease-free survival (DFS) starting from the time of surgery was calculated by the Kaplan-Meier method, and log-rank tests were performed to compare DFS between patients with superior and inferior tumor response. Results: Overall, 185 LARC patients received nCRT, of whom 89 (48.11%) achieved superior tumor response. Diminutive pGTV (p = 0.038) and distance from the anal verge (DAV) (p = 0.006) were independent predictive factors of superior tumor response. Meanwhile, pGTV can be regarded as an independent predictor of pathologic complete response (pCR) (p = 0.036). The log-rank test revealed that DFS was longer in the diminutive pGTV group than in the giant pGTV group (p = 0.001). Conclusions: pGTV, as a measure of tumor size, is not only an important prognostic indicator but also an independent predictive factor of tumor response, even pCR.

Nomograms predicting Overall Survival and Cancer-specific Survival for Synchronous Colorectal Liver-limited Metastasis.

Background: Colorectal cancer (CRC) ranks as the third most frequent cancer type and the second leading cause of cancer-related death worldwide. The liver is the most common metastatic site of CRC with 20%-34% of patients suffering synchronous liver metastasis. Patients with colorectal liver-limited metastasis account for one-third of deaths from colorectal cancer. Moreover, some evidence indicated that CRC patients with synchronous liver disease encounter a worse prognosis and more disseminated disease state comparing with metastatic liver disease that develops metachronously. Methods: Data in this retrospective analysis were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Nomograms were constructed with basis from a multivariate Cox regression analysis. The prognostic nomograms were validated by C-index, time-dependent receiver operating characteristic (ROC) curve, decision curve analysis (DCA) and calibration curves. Results: A total of 9,958 CRC patients with synchronous liver-limited metastasis were extracted from the SEER database during 2010-2016. Both overall survival (OS) and cancer-specific survival (CSS) were significantly correlated with age, marital status, race, tumor location, pathological grade, histologic type, T stage, N stage, surgery for primary tumor, surgery for liver metastasis, chemotherapy and CEA. All of the significant variables were used to create the nomograms predicting OS and CSS. C-index values, time-dependent ROC curves, DCA curves and calibration curves, proved the superiority of the nomograms. Conclusions: Our research investigated a national cohort of almost 10,000 patients to create and verify nomograms based on pathological, therapeutic and demographic features to predict OS and CSS for synchronous colorectal liver-limited metastasis (SCLLM). The nomograms may act as an excellent tool to integrate clinical characteristics to guide the therapeutic choice for SCLLM patients.

A bibliometric analysis of 23,492 publications on rectal cancer by machine learning: basic medical research is needed.

BACKGROUND AND AIMS: The aim of this study was to analyse the landscape of publications on rectal cancer (RC) over the past 25 years by machine learning and semantic analysis. METHODS: Publications indexed in PubMed under the Medical Subject Headings (MeSH) term 'Rectal Neoplasms' from 1994 to 2018 were downloaded in September 2019. R and Python were used to extract publication date, MeSH terms and abstract from the metadata of each publication for bibliometric assessment. Latent Dirichlet allocation was applied to analyse the text from the articles' abstracts to identify more specific research topics. Louvain algorithm was used to establish a topic network resulting in identifying the relationship between the topics. RESULTS: A total of 23,492 papers published were identified and analysed in this study. The changes of research focus were analysed by the changing of MeSH terms. Studied contents extracted from the publications were divided into five areas, including surgical intervention, radiotherapy and chemotherapy intervention, clinical case management, epidemiology and cancer risk as well as prognosis studies. CONCLUSIONS: The number of publications indexed on RC has expanded rapidly over the past 25 years. Studies on RC have mainly focused on five areas. However, studies on basic research, postoperative quality of life and cost-effective research were relatively lacking. It is predicted that basic research, inflammation and some other research fields might become the potential hotspots in the future.

Mcl-1 inhibition overcomes intrinsic and acquired regorafenib resistance in colorectal cancer.

Intrinsic and acquired resistance to targeted therapies is a significant clinical problem in cancer. We previously showed that resistance to regorafenib, a multi-kinase inhibitor for treating colorectal cancer (CRC) patients, can be caused by mutations in the tumor suppressor FBW7, which block degradation of the pro-survival Bcl-2 family protein Mcl-1. We tested if Mcl-1 inhibition can be used to develop a precision combination therapy for overcoming regorafenib resistance. METHODS: Small-molecule Mcl-1 inhibitors were tested on CRC cells with knock-in (KI) of a non-degradable Mcl-1. Effects of Mcl-1 inhibitors on regorafenib sensitivity were determined in FBW7-mutant and -wild-type (WT) CRC cells and tumors, and in those with acquired regorafenib resistance due to enriched FBW7 mutations. Furthermore, translational potential was explored by establishing and analyzing FBW7-mutant and -WT patient-derived organoid (PDO) and xenograft (PDX) tumor models. RESULTS: We found that highly potent and specific Mcl-1 inhibitors such as S63845 overcame regorafenib resistance by restoring apoptosis in multiple regorafenib-resistant CRC models. Mcl-1 inhibition re-sensitized CRC tumors with intrinsic and acquired regorafenib resistance in vitro and in vivo, including those with FBW7 mutations. Importantly, Mcl-1 inhibition also sensitized FBW7-mutant PDO and PDX models to regorafenib. In contrast, Mcl-1 inhibition had no effect in FBW7-WT CRCs. CONCLUSIONS: Our results demonstrate that Mcl-1 inhibitors can overcome intrinsic and acquired regorafenib resistance in CRCs by restoring apoptotic response. FBW7 mutations might be a potential biomarker predicting for response to the regorafenib/Mcl-1 inhibitor combination.

Propranolol Suppresses the Growth of Colorectal Cancer Through Simultaneously Activating Autologous CD8+ T Cells and Inhibiting Tumor AKT/MAPK Pathway.

Propranolol suppresses tumor growth in a variety of preclinical solid tumor models, with a number of proposed cell signaling and immunological mechanisms. We want to confirm the potential mechanisms, including reduced phosphorylation of AKT/MAPK pathways, as well as enhanced CD8+ T-cell-mediated antitumor immune response. To clarify the mechanism of propranolol activity in colorectal cancer, the therapeutic activity of propranolol was then assessed in CT26WT tumors engrafted in BALB/C mice. Then the effect of propranolol treatment was also examined by randomizing patients undergoing surgical resection of a previously untreated colorectal cancer to propranolol or placebo group and treated for 1 week prior to surgery. CT26WT tumor size was smaller after propranolol than vehicle control. Propranolol downregulated the expression of p-AKT/p-ERK/p-MEK in tumor tissue. The frequency of tumor CD8+ T cells was significantly elevated in propranolol-treated mice. The expression of GzmB/IFN-γ/T-bet in the CD8+ T-cell population was significantly increased in propranolol treated mice tumor tissue. In propranolol-treated surgical specimens, the expression of p-ERK was decreased and the frequency of CD8+ was significantly elevated. The expression of GzmB in the CD8+ T-cell population was significantly increased in propranolol-treated subjects. Together, these data show propranolol simultaneously activating autologous CD8+ T cells and decreasing the expression of p-AKT/p-ERK/p-MEK in mouse tumor models, while inhibiting the expression of p-ERK in clinical colorectal cancer. Effort is now needed to further dissect whether both pathways are required for antitumor effect, as the activity of this old drug is moved forward.

Matrix Stiffness and Colorectal Cancer.

In recent years, a growing consensus is emerging that the mechanical microenvironment of tumors is far more critical in the onset of tumor, tumor progression, invasion, and metastasis. Matrix stiffness, one of the sources of mechanical stimulation, affects tumor cells as well as non-tumor cells in multiple different molecular signaling pathways in solid tumors such as colorectal tumors, which lead to tumor invasion and metastasis, immune evasion and drug resistance. This review will illustrate the relationship between matrix stiffness and colorectal cancer from the following aspects. First, briefly introduce the mechanical microenvironment and colorectal cancer, then explain the origin of colorectal cancer extracellular matrix stiffness, and then synthesize the study of matrix stiffness of colorectal cancer in recent years to elaborate the effects of extracellular matrix stiffness in colorectal cancer's biological behavior and signaling pathways, and finally we will discuss the transformation treatment for the matrix stiffness of colorectal cancer. An in-depth understanding of matrix stiffness and colorectal cancer can help researchers conduct further experiments to find new targets for the treatment of colorectal cancer.

Functional polymorphism of PIN1 rs2233679 is associated with the progression of CIN to early cervical cancer in Hunan Chinese.

OBJECTIVE: Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (PIN1) involves alteration of the structure, function, intracellular localization and/or stability of the phosphorylated protein on serine or threonine residues which relates to inflammation and tumorigenesis. Association between PIN1 promoter polymorphisms and cancer risk were reported in several cancers. We intend to study the relationship between the polymorphism of PIN1 promoter and cervical cancer initiation and development. MATERIALS AND METHODS: We genotyped two common single nucleotide polymorphisms (SNPs) (rs2233678 and rs2233679) in the promoter of the PIN1 gene in healthy controls, patients with CIN or cervical cancer. We used polymerase chain reaction and DNA sequencing methods to analyze these two SNPs in 179 patients and 223 healthy controls. Luciferase activity assay was used to detect PIN1 expression driven by the rs2233679. RESULTS: The results revealed that the carriers of rs2233679 genotypes CT/TT had a significantly increased risk of cervical cancer in patients with CIN compared with genotype CC (odds ration [OR] = 2.924, 95% confidence interval [CI] = 1.093-7.819, P = 0.033). Luciferase activity assay results revealed that PIN1 expression driven by the rs2233679 genotype TT was higher than the genotype CC (P < 0.05). On the other hand, no significant correlation between the healthy controls and patients was found for PIN1 rs2233678 which showed that rs2233678 genotypes CG/GG is 95% in healthy controls and 100% in patients. CONCLUSION: PIN1 rs2233679 genotype CT/TT may be a risk factor of early cervical cancer compared with genotype CC in Hunan populations. Our findings suggest that PIN1 rs2233679 genotype CT/TT might involve in the progression of the precancerous stage developing to early cancer by enhancing PIN1 expression.