The Role of Neuropilin-2 in the Epithelial to Mesenchymal Transition of Colorectal Cancer: A Systematic Review

Neuropilin-2 (NRP-2) expression has been found in various investigations on the expression and function of NRP-2 in colorectal cancer. The link between NRP-2 and colorectal cancer, as well as the mechanism that regulates it, is still mostly unclear. This systematic review was carried out according to the Cochrane guidelines for systematic reviews. We searched PubMed, Embase®, MEDLINE, Allied & Complementary MedicineTM, Medical Toxicology & Environmental Health, DH-DATA: Health Administration for articles published before 1 October 2021. The following search terms were used: “neuropilin-2” “neuropilin 2”, “NRP2” and “NRP-2”, “colorectal cancer”, “colon cancer”. Ten articles researching either tumor tissue samples, cell lines, or mice models were included in this review. The majority of human primary and metastatic colon cancer cell lines expressed NRP-2 compared to the normal colonic mucosa. NRPs have been discovered in human cancers as well as neovasculature. The presence of NRP-2 appears to be connected to the epithelial–mesenchymal transition’s function in cancer dissemination and metastatic evolution. The studies were heterogeneous, but the data assessed indicates NRP-2 might have an impact on the metastatic potential of colorectal cancer cells. Nevertheless, further research is needed.

he effects of NETosis on fibrinolysis in colon cancer patients

Aim. To investigate formation of neutrophil extracellular traps (NETs) and their impact on fibrinolysis in patients with colon cancer.Materials and methods. The study was performed in two groups. The experimental group consisted of patients with stage 2–3 non-metastatic colon cancer (n = 17, average age – 67 years). The control group included healthy volunteers matched by sex and age (n = 30, average age – 68 years). An experimental model was created from the whole blood. It included platelet-poor plasma and an isolated culture of neutrophils, previously induced to NETosis by adding 100 nmol PMA. The samples were incubated for 4 hours, then the test tubes were centrifuged to pellet cells and their remnants, and the plasma was transferred for subsequent examination. The plasma incubated with intact neutrophils was used as a control. The levels of interleukin-8 (IL-8) and P-selectin glycoprotein ligand-1 (PSGL-1) were used to determine the degree of cell activation. NETosis was confirmed by enzyme-linked immunosorbent assay (ELISA) and fluorescent microscopy. Fibrinolysis was assessed using the thrombodynamics test. The results were compared with the levels of fibrinolytic system components measured by flow cytometry.Results. In the control group, NETosis induction contributed to pronounced neutrophil activation that was accompanied by an increase in the IL-8, PSGL-1, and plasminogen levels, a decrease in PAI-1, and enhancement of fibrinolysis, compared with the intact samples. Higher levels of IL-8, PSGL-1, plasminogen, and PAI-1 and intensified fibrinolysis were detected in the intact samples. However, PMA-induced NETosis did not result in an increase in the degree of activation and significant changes in the given parameters.Conclusion. NETosis promotes both formation and lysis of fibrin clots. However, in cancer patients, suicidal NETosis does not contribute to fibrinolysis due to intracellular protease depletion, which may be one of the mechanisms causing hypercoagulation and insufficient fibrinolysis in cancer.

Effect of pentoxifylline on colon cancer patients treated with chemotherapy (Part I)

BACKGROUND: Cancer progression is associated with significant systemic clinical manifestations including cachexia induced weight loss and anorexia. Pentoxifylline (PTX) is a drug that has been shown to have multiple beneficial effects in cancer patients through its anti-inflammatory properties. MAIN OBJECTIVE: To evaluate PTX effects on colon cancer patients treated with chemotherapy. PATIENTS and METHODS: Forty metastatic colon cancer patients receiving chemotherapy were enrolled in this randomized study. 17 patients were treated with a full dose of PTX (400 mg TID), 9 patients with a reduced dose PTX (200 mg TID) and 23 served as controls (no PTX). RESULTS: Follow-up evaluations of patients included the following: physical examination; leukopenia determination; weight determination; stomatitis determination; and survival rate. Patients treated with PTX (both full and reduced doses), experienced a significant increase in weight and a reduction in stomatitis relative to the control group. Treatment with PTX also significantly increased patient survival rate. All patients treated with PTX, had a median overall survival (OS) rate of 20.4 months as compared to 13.2 months in the control group. CONCLUSIONS: PTX treatment of colon cancer patients, in addition to chemotherapy, significantly improved survival rates, induced weight gain and reduced stomatitis occurrence –all important parameters of cachexia.

Influence of oxygen availability on expression of glutaminolysis genes in human colon cancer cells

Introduction Glutaminolysis, beside glycolysis, is a key metabolic pathway of a cancer cell that provides energy and substrates for the synthesis of nucleic acids, proteins, and lipids. The pathway is mediated by both mitochondrial and cytosolic enzymes. Neither expression of glutaminolysis enzymes in colon cancer cells nor the influence of various oxygen concentrations on their expression has been studied so far. Objectives The aim of the study was to determine and compare the mRNA expression of enzymes involved in glutaminolysis at various oxygen levels in human primary (SW480) and metastatic (SW620) colon cancer cells cultured in 1% O2 (hypoxia), 10% O2 (tissue normoxia), 21% O2 (atmospheric normoxia). Methods Cell viability was determined by Trypan Blue exclusion (TB) and Thiazolyl Blue Tetrazolium Bromide (MTT). The expression of HIF1α, GLUT1, GLS1, AST1, AST2, ACL, PC and GC1, GC2 at mRNA levelwas determined by RT-qPCR. Results. Correlation between increasing oxygen concentration and cell count was not observed. In both cell lines the number of viable cells was the lowest at 10% oxygen. The enzyme profile and expression of proteins involved in glutaminolysis varied depending on oxygen pressure and type of cell lines. In summary, our findings suggest differences in metabolic adaptation to oxygen availability in vivo between primary and metastatic colon cancer cells.

Modeling of Personalized Treatments in Colon Cancer Based on Preclinical Genomic and Drug Sensitivity Data

The current standard therapies for advanced, recurrent or metastatic colon cancer are the 5-fluorouracil and oxaliplatin or irinotecan schedules (FOxFI) +/− targeted drugs cetuximab or bevacizumab. Treatment with the FOxFI cytotoxic chemotherapy regimens causes significant toxicity and might induce secondary cancers. The overall low efficacy of the targeted drugs seen in colon cancer patients still is hindering the substitution of the chemotherapy. The ONCOTRACK project developed a strategy to identify predictive biomarkers based on a systems biology approach, using omics technologies to identify signatures for personalized treatment based on single drug response data. Here, we describe a follow-up project focusing on target-specific drug combinations. Background for this experimental preclinical study was that, by analyzing the tumor growth inhibition in the PDX models by cetuximab treatment, a broad heterogenic response from complete regression to tumor growth stimulation was observed. To provide confirmation of the hypothesis that drug combinations blocking alternatively activated oncogenic pathways may improve therapy outcomes, 25 models out of the well-characterized ONCOTRACK PDX panel were subjected to treatment with a drug combination scheme using four approved, targeted cancer drugs.

Comparison of Vascular Invasion With Lymph Node Metastasis as a Prognostic Factor in Stage I-III Colon Cancer: An Observational Cohort Study

Purpose: This study aimed to evaluate the prognostic impact of vascular invasion (VI) in comparison with that of lymph node metastasis (LNM) in non-metastatic colon cancer.Methods: Patients who underwent curative surgery for stage I-III colon cancer were divided into four groups depending on the status of VI and LNM (Group I: VI-/LNM-; Group II: VI+/LNM-; Group III: VI-/LNM+; Group IV: VI+/LNM+). Group III was subdivided according to the nodal (N) stage (Group IIIA: VI-/N1; Group IIIB: VI-/N2). Oncological outcomes were compared between Groups II and III.Results: In total, 793 non-metastatic colon cancer patients were included. Group II [hazard ratio (HR) 2.34, 1.01–5.41] and Group III (HR 1.91, 1.26–2.89) were independently associated with poor disease-free survival (DFS). The 5-year DFS rates were comparable in Groups II (71.6%) and III (72.5%) (P = 0.637). When Group III was subdivided into Groups IIIA and IIIB, DFS deteriorated in the following order: Groups IIIA, II, and IIIB. The 5-year DFS rates were 79.7, 71.6, and 61.4% in Groups IIIA, II, and IIIB, respectively. Group II had a tendency toward early recurrence. The 1- and 2-year DFS rates were 76.3 and 71.6% in Group II and 88.3 and 79.8% in Group III, respectively (P = 0.067 and 0.247). All recurrences in Group II were distant metastases.Conclusion: VI is a prognostic factor as significant as LNM and may be a stronger prognostic factor than N1 stage in non-metastatic colon cancer. Furthermore, a potential association was observed between VI and recurrence patterns, such as early recurrence and distant metastasis.