Background: Lactate accumulation leads to an acidic tumor microenvironment (TME), in turn promoting colorectal cancer (CRC) progression. Tumor-associated macrophages (TAMs) are the predominant cells in TME. This study aimed to reveal the regulation mechanism of CRC cell-derived lactate on TAMs and explore the mechanism underlying lactate accumulation-induced aggravation in CRC. Methods: Cell growth and metastasis were evaluated by colony formation, Transwell, and wound healing assays. Western blot and RT-qPCR were applied to determine the protein and mRNA expression. Flow cytometry was used to analyze the polarization state and apoptotic rate of macrophages induced in THP-1 cells. The lactate in the cell supernatant was quantified using an ELISA kit. Immunofluorescence was performed to visualize the location of High Mobility Group Box 1 (HMGB1). H&E and Ki67 staining assays were used to assess tumorigenesis in nude mice bearing ectopic tumors. Results: Cell growth and metastasis were promoted in the hypoxic CRC cells. The hypoxic cell supernatant stimulated the M2-type polarization of macrophages. The lactate level increased in hypoxic cancer cells. However, the inhibition of lactate using 3-hydroxy-butyrate (3-OBA) reversed the effects of hypoxia. Also, macrophages showed no promoting effect on cancer cell growth and migration in the presence of 3-OBA. HMGB1 was secreted into the extracellular space of lactate-induced macrophages, further enhancing the malignant behaviors of cancer cells. ERK, EMT, and Wnt signaling pathways were activated in cancer cells due to HMGB1 upregulation. Conclusions: The lactate metabolized by cancer cells stimulated M2 polarization and HMGB1 secretion by macrophages, aggravating the carcinogenic behaviors of cancer cells.

Circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) provides a powerful approach to predict recurrence in colorectal cancer (CRC) and potentially improve survival outcomes for individuals diagnosed with CRC. Currently, there are two primary technical approaches for the detection of MRD using ctDNA: the tumor-informed assays and the tumor-agnostic assays. Multiple studies have demonstrated the role of MRD detection in CRC patients after radical therapy, including early relapse monitoring, molecular profiling, and treatment response prediction. Numerous interventional clinical trials based on ctDNA are underway to explore the value of MRD in optimizing adjuvant treatment decisions for patients with CRC. Once validated, ctDNA-MRD has the potential to impact current clinical treatment decisions. In this review, we summarize current techniques for detecting MRD based on ctDNA and review the data that have been collected to date on MRD detection in CRC patients who received curative-intent therapy. We also discuss prospective research of ctDNA MRD detection in this patient population and provide guidelines for the current and future use of MRD in clinical practice.

Colorectal cancer (CRC) is a highly prevalent malignancy and a leading cause of cancer-related mortality globally, necessitating the exploration of innovative diagnostic and therapeutic strategies alongside conventional approaches such as surgery, chemotherapy, and radiotherapy which exhibit inherent limitations. This review systematically examines recent advancements in CRC research, particularly focusing on early diagnostic methodologies, novel surgical techniques, advancements in radiotherapy and chemotherapy, as well as the burgeoning fields of immunotherapy and targeted therapies. A comprehensive search of the PubMed database was conducted to collate key clinical studies published over the last three years in order to assess the current landscape of CRC management. The results emphasize the paramount importance of early diagnosis and innovative surgical strategies while highlighting significant progress in radiotherapy and chemotherapy, with immunotherapy and targeted treatments emerging as promising avenues. Notably, the increasing incidence of aggressive early-onset colorectal cancer (EO-CRC) reinforces the urgent need for effective screening and prevention frameworks, supplemented by interdisciplinary treatment teams that are crucial for optimal patient management. Enhanced pathological diagnosis is vital for informing adjuvant chemotherapy decisions, and ongoing advancements in surgical methods and systemic therapies are contributing to improved patient outcomes. Furthermore, the potential of personalized cancer therapy through targeted approaches presents an exciting frontier, though further investigation is essential to better delineate candidate identification for immunotherapy. Targeted sequencing panels could play a pivotal role in optimizing patient selection for these emerging therapies, thereby augmenting CRC treatment strategies in the future.

Background: Colon cancer (CRC) is a common type of tumour, and IQGAP family proteins play an important role in many tumours. However, their roles in CRC remain unclear. Methods: First, we searched many public databases to comprehensively analyze expression of IQGAPs in CRC. Next, real-time PCR, immunohistochemical (IHC), transwell, siRNA transfection and Western blot assays were used to evaluate relationships among IQGAP3 expression, clinical pathological parameters and CRC prognosis, and the underlying molecular mechanism was investigated. Results: IQGAP3 was elevated in CRC tissues, whereas there was no significant change in expression of IQGAP1 or IQGAP2. Additionally, IQGAP3 expression in CRC tissues was associated with tumour progression, invasion and poor prognosis. In mechanistic studies, we found that IQGAP3 was positively coexpressed with PIK3C2B. In an in vitro assay, the PIK3C2B expression level was increased after exogenous overexpression of IQGAP3, resulting in the promotion of cell invasion, which was blocked by pretransfecting cells with PIK3C2B siRNA. Furthermore, we found that high expression of IQGAP3 and PIK3C2B correlated with tumour stage and vessel invasion in human CRC, whereby patients with high expression of both in tumours had a worse prognosis compared with patients with single-positive or double-negative tumours. Conclusion: The results of our current study and corresponding previous studies provide evidence that IQGAP3 is elevated in CRC and promotes colon cancer growth and metastasis by regulating PIK3C2B activation.

Background: Regional lymph node metastasis (LNM) is crucial for planning additional lymphadenectomy, and is directly correlated with poor prognosis in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). However, the patterns of LNM for small (≤20 mm) GEP-NETs remain unclear. This population-based study aimed at evaluating LNM patterns and identifying optimal surgical strategies from the standpoint of lymph node dissemination.Methods: This retrospective cohort study retrieved data from the Surveillance, Epidemiology, and End Results (SEER) 18 registries database for 17,308 patients diagnosed as having localized well-differentiated GEP-NETs ≤ 20 mm between January 1, 2004, and December 31, 2017. The patterns of LNM were characterized in 6,622 patients who underwent extended resection for adequate lymph node harvest.Results: Of 6,622 patients with localized small GEP-NETs in the current study, 2,380 (36%) presented with LNM after regional lymphadenectomy. Nodal involvement was observed in approximately 7.4%, 49.1%, 13.6%, 53.7%, 13.8%, 7.8%, and 15.4% of gastric (g-), small intestinal (si-), appendiceal (a-), colonic (c-), rectal (r-), non-functional pancreatic (nfp-), and functional pancreatic (fp-) NETs ≤ 20 mm. Patients with younger age, larger tumor size, and muscularis invasion were more likely to present with LNM. Additional lymphadenectomy conferred a significant survival advantage in NETs (≤10 mm: HR, 0.47; 95% CI, 0.33–0.66; p < 0.001; 11–20 mm: HR, 0.54; 95% CI, 0.34–0.85; p = 0.008) and fp-NETs ≤ 20 mm (HR, 0.08; 95% CI, 0.02–0.36; p = 0.001), as well as g-NETs (HR, 0.39; 95% CI, 0.16–0.96; p = 0.041) and c-NETs of 11–20 mm (HR, 0.07; 95% CI, 0.01–0.48; p = 0.007). Survival benefits of additional lymphadenectomy were not found in a-NETs, r-NETs, and nfp-NETs with a small size.Conclusions: Given the increased risk for nodal metastasis, primary tumor resection with regional lymphadenectomy is a potential optimal surgical strategy for si-NETs and fp-NETs ≤ 20 mm, as well as g-NETs and c-NETs of 11–20 mm. Local resection is an appropriate and reliable surgical approach for a-NETs, r-NETs, and nfp-NETs ≤ 20 mm.

Checkpoint kinase 1 (CHK1) and p53 are involved in cell‑cycle checkpoint, and cellular response to DNA damage. CHK1 and p53 are overexpressed in bladder urothelial carcinoma (BUC); however, a clear elucidation on their interaction and influence in the progress of BUC is absent. The aim of the present study was to examine the correlation between CHK1 and p53 in BUC, and analyze their value as therapeutic targets and prognostic indicators in BUC. A clinically annotated cohort of 110 patients with BUC was identified retrospectively. EnVision‑based immunohistochemistry and western blot analysis of the aforementioned DNA repair proteins were conducted on formalin‑fixed‑paraffin‑embedded or frozen tissues from the primary tumor. A total of 45 peritumoral tissue cases were assessed similarly as the control group. In the cohort of 110 patients with BUC, a significant overexpression of CHK1 and p53 was observed in primary compared with the peritumoral tissues (P<0.05). CHK1 and p53 demonstrated a positive correlation in BUC, and both were positively associated with the histological grade, clinical pathological staging, lymphatic metastasis and the 5‑year survival rate (P<0.05). However, CHK1 and p53 were not associated with sex, age, tumor diameter, single/multiple sites or incipient/recurrence. The overexpression of CHK1 and p53, and their synergistic interaction were putatively correlated with the physiology of BUC that may be deemed as potential therapeutic targets and prognostic indicators.