Use of Patient-Derived Organoids as a Treatment Selection Model for Colorectal Cancer: A Narrative Review.

Surgical resection is the mainstay in intended curative treatment of colorectal cancer (CRC) and may be accompanied by adjuvant chemotherapy. However, 40% of the patients experience recurrence within five years of treatment, highlighting the importance of improved, personalized treatment options. Monolayer cell cultures and murine models, which are generally used to study the biology of CRC, are associated with certain drawbacks; hence, the use of organoids has been emerging. Organoids obtained from tumors display similar genotypic and phenotypic characteristics, making them ideal for investigating individualized treatment strategies and for integration as a core platform to be used in prediction models. Here, we review studies correlating the clinical response in patients with CRC with the therapeutic response in patient-derived organoids (PDO), as well as the limitations and potentials of this model. The studies outlined in this review reported strong associations between treatment responses in the PDO model and clinical treatment responses. However, as PDOs lack the tumor microenvironment, they do not genuinely account for certain crucial characteristics that influence therapeutic response. To this end, we reviewed studies investigating PDOs co-cultured with tumor-infiltrating lymphocytes. This model is a promising method allowing evaluation of patient-specific tumors and selection of personalized therapies. Standardized methodologies must be implemented to reach a "gold standard" for validating the use of this model in larger cohorts of patients. The introduction of this approach to a clinical scenario directing neoadjuvant treatment and in other curative and palliative treatment strategies holds incredible potential for improving personalized treatment and its outcomes.

The gut microbiota can orchestrate the signaling pathways in colorectal cancer.

Current evidence suggests that bacteria contribute to the development of certain cancers, such as colorectal cancer (CRC), partly by stimulating chronic inflammation. However, little is known about the bacterial impact on molecular pathways in CRC. Recent studies have demonstrated how specific bacteria can influence the major CRC-related pathways, i.e., Wnt, PI3K-Akt, MAPK, TGF-ß, EGFR, mTOR, and p53. In order to advance the current understanding and facilitate the choice of pathways to investigate, we have systematically collected and summarized the current knowledge within bacterial altered major pathways in CRC. Several pro-tumorigenic and anti-tumorigenic bacterial species and their respective metabolites interfere with the major signaling pathways addressed in this review. Not surprisingly, some of these studies investigated known CRC drivers, such as Escherichia coli, Fusobacterium nucleatum, and Bacteroides fragilis. Interestingly, some metabolites produced by bacterial species typically considered pathogenic, e.g., Vibrio cholera, displayed anti-tumorigenic activities, emphasizing the caution needed when classifying healthy and unhealthy microorganisms. The results collectively emphasize the complexity of the relationship between the microbiota and the tumorigenesis of CRC, and future studies should verify these findings in more realistic models, such as organoids, which constitute a promising platform. Moreover, future trials should investigate the clinical potential of preventive modulation of the gut microbiota regarding CRC development.

Colonic Stent as Bridge to Surgery for Malignant Obstruction Induces Gene Expressional Changes Associated with a More Aggressive Tumor Phenotype.

BACKGROUND: Colonic stent is recommended as a bridge to elective surgery for malignant obstruction to improve short-term clinical outcomes for patients with colorectal cancer. However, since the oncological outcomes remain controversial, this study aimed to investigate the impact of self-expandable metallic stent (SEMS) on the tumor microenvironment. METHODS: Patients treated with colonic stent as a bridge to surgery from 2010 to 2015 were identified from hospital records. Tumor biopsies and resected tumor samples of the eligible patients were retrieved retrospectively. Gene expression analysis was performed using the NanoString nCounter PanCancer IO 360 gene expression panel. RESULTS: Of the 164 patients identified, this study included 21 who underwent colonic stent placement as a bridge to elective surgery. Gene expression analysis revealed 82 differentially expressed genes between pre- and post-intervention specimens, of which 72 were upregulated and 10 downregulated. Among the significantly upregulated genes, 46 are known to have protumor functions, of which 26 are specifically known to induce tumorigenic mechanisms such as proliferation, migration, invasion, angiogenesis, and inflammation. In addition, ten differentially expressed genes were identified that are known to promote antitumor functions. CONCLUSION: SEMS induces gene expressional changes in the tumor microenvironment that are associated with tumor progression in colorectal cancer and may potentiate a more aggressive phenotype. Future studies are warranted to establish optimal timing of surgery after SEMS insertion in patients with obstructive colorectal cancer.