Hypoxic tumor microenvironment activates GLI2 via HIF-1α and TGF-ß2 to promote chemoresistance in colorectal cancer.

Colorectal cancer patients often relapse after chemotherapy, owing to the survival of stem or progenitor cells referred to as cancer stem cells (CSCs). Although tumor stromal factors are known to contribute to chemoresistance, it remains not fully understood how CSCs in the hypoxic tumor microenvironment escape the chemotherapy. Here, we report that hypoxia-inducible factor (HIF-1α) and cancer-associated fibroblasts (CAFs)-secreted TGF-ß2 converge to activate the expression of hedgehog transcription factor GLI2 in CSCs, resulting in increased stemness/dedifferentiation and intrinsic resistance to chemotherapy. Genetic or small-molecule inhibitor-based ablation of HIF-1α/TGF-ß2-mediated GLI2 signaling effectively reversed the chemoresistance caused by the tumor microenvironment. Importantly, high expression levels of HIF-1α/TGF-ß2/GLI2 correlated robustly with the patient relapse following chemotherapy, highlighting a potential biomarker and therapeutic target for chemoresistance in colorectal cancer. Our study thus uncovers a molecular mechanism by which hypoxic colorectal tumor microenvironment promotes cancer cell stemness and resistance to chemotherapy and suggests a potentially targeted treatment approach to mitigating chemoresistance.

A lower cut-off for lymph node harvest predicts for poorer overall survival after rectal surgery post neoadjuvant chemoradiotherapy.

BACKGROUND: A lymph node harvest (LNH) of < 12 is a predictor for poor prognosis in rectal cancer patients. However, neoadjuvant chemoradiotherapy (NACRT) is known to decrease LNH; hence, a cut-off of 12 is inappropriate in such patients. This paper aims to establish a LNH cut-off predictive for disease-free and overall survival in NACRT patients. METHODS: A retrospective review of patients who underwent elective surgery for rectal cancer from 2006 to 2013 was performed. All patients with R1/2 resections and presence of metastases and those operated on for recurrence were excluded. Patient demographics, clinical features, operative details, LNH, 30-day mortality and disease-free and overall survival were recorded. P values of < 0.05 were considered significant. RESULTS: A total of 257 patients were studied, with 174 (68%) males and a median age of 66 years. Ninety-four (37%) patients received long-course NACRT, and 122 (48%) patients were stage 2 and below. Median LNH was 17, which was reduced in the NACRT group (14 versus 23, P < 0.01). Average length of stay was 9 ± 8 days, with a major post-operative complication rate of 4%. Using hazard ratio plots for the NACRT subgroup, LNH cut-offs of 16.5 and 8.5 were obtained for disease-free survival (DFS) and overall survival (OS) respectively. Survival analysis showed that a LNH cut-off of 8.5 was a significant predictor of OS (P < 0.001). CONCLUSION: LNH is reduced in patients receiving NACRT before rectal cancer surgery. A LNH of 9 and above is associated with improved overall survival. We propose that this can be used as a tool for prognosis.

Short Term Postoperative and Oncological Outcomes of Two-Dimensional Versus Three-Dimensional Laparoscopic Transanal Total Mesorectal Excision of Rectal Cancer.

Background: Transanal total mesorectal excision (TaTME) carried out synchronously with laparoscopy is a useful surgical technique in rectal cancer patients who are overweight or who have a narrow pelvis. This retrospective study aims to compare the safety and efficacy of two-dimensional (2D) and three-dimensional (3D) laparoscopic TaTME of rectal cancer based on the short-term postoperative and oncological outcomes of 40 patients in Singapore who underwent laparoscopic TaTME. Materials and Methods: Forty patients underwent laparoscopic TaTME for rectal cancer in one of three centers in Singapore from October 2015 to August 2018. Out of these patients, 23 underwent 3D laparoscopic TaTME with the Olympus Flexible Tip™ 10 mm scope. Data on patient demographics, operative details, and postoperative and oncological outcomes were collected retrospectively by going through soft copy patient records, analyzed and compared. Results: The operative time for 3D group was significantly shorter (340 versus 419 minutes, P = .04). Complete TME grade and R0 resection was achieved in a higher percentage of patients in the 3D group although this was not statistically significant. There were no other significant differences between the two groups in terms of oncological outcomes and other short-term postoperative outcomes. Discussion and Conclusion: TaTME is overall a safe technique. Three-dimensional TaTME for rectal cancers is as safe and feasible as 2D TaTME, with the advantage of a shorter operative time.