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Introduction: Individuals with Familial Adenomatous Polyposis (FAP) or APC -associated polyposis, an autosomal dominant inherited condition, develop multiple adenomatous polyps and have an increased colorectal cancer (CRC) risk. A change in diet can help reduce cancer risk, and several dietary components have an antitumor effect. We aimed to evaluate the potential of the anti-inflammatory and anticancer substances quercetin (QER), epigallocatechin gallate (EGG) and fisetin (FIS) in decreasing the risk of CRC by reducing the growth of polyps in an organoid model., Methods: Patient-derived organoid (PDO) lines were generated from polyps obtained from patients with FAP undergoing prophylactic colectomy. PDOs were treated with QER, EGG, or FIS to determine their effect on cell growth. Changes in caspase 3/7 activity and expression of inflammation and apoptosis mediators were assessed by luminescent and colorimetric assays., Results: Three PDO lines with different inactivating pathogenic variants in the APC gene were developed using a combinatorial approach. FIS was the most active of the three substances tested, presenting the lowest IC50 in all PDO lines (range: 42.6-9.2 uM). The IC50 was defined as the concentration required to halve the number of cells after 72 hours. All molecules tested induced apoptosis through activation of caspases 3/7., Conclusions: QER, EGG, and FIS can be easily taken from foods or dietary supplements, show toxicity on PDOs derived from adenomatous polyps, while they are known to be harmless on normal cells. Diets enriched with these substances could be potential supplemental treatments to reduce the risk of CRC in individuals with FAP., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Objectives: Few preclinical models of pseudomyxoma peritonei (PMP) have been developed, probably due to the tumor's low incidence and its peculiar characteristics of slow growth. Therefore, there is a need to develop more refined PMP models that better reflect its characteristics. The aim of the study is to develop a culture strategy to generate organoid models derived from PMP patient samples., Methods: We followed a strategy based on combinatorial culture conditions that include the different factors essential for PMP growth and that mimic the microenvironment present in the patients., Results: We cultured PMP samples in the presence of the various factors produced by the niche environment of PMP. We obtained 12 PMP organoid models, each of which grows under specific culture conditions. PMP-derived organoids show long-term expansion capacity and reproduce the genetic landscape and histological phenotype of the tumor of origin., Conclusion: The organoids we developed faithfully reproduce the key features of PMP disease and will allow us to understand the biology of PMP. With them, we will be able to identify key regulatory networks that support PMP progression, providing a platform for multilevel preclinical testing, identify novel diagnostic biomarkers, and generate novel targets for patient treatments., (© 2024 The Author(s). Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Background: Peritoneal metastases from colorectal cancer (CRCPM) are related to poor prognosis. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been reported to improve survival, but peritoneal recurrence rates are still high and there is no consensus on the drug of choice for HIPEC. The aim of this study was to use patient derived organoids (PDO) to build a relevant CRCPM model to improve HIPEC efficacy in a comprehensive bench-to-bedside strategy., Methods: Oxaliplatin (L-OHP), cisplatin (CDDP), mitomycin-c (MMC) and doxorubicin (DOX) were used to mimic HIPEC on twelve PDO lines derived from twelve CRCPM patients, using clinically relevant concentrations. After chemotherapeutic interventions, cell viability was assessed with a luminescent assay, and the obtained dose-response curves were used to determine the half-maximal inhibitory concentrations. Also, induction of apoptosis by different HIPEC interventions on PDOs was studied by evaluating CASPASE3 cleavage., Results: Response to drug treatments varied considerably among PDOs. The two schemes with better response at clinically relevant concentrations included MMC alone or combined with CDDP. L-OHP showed relative efficacy only when administered at low concentrations over a long perfusion period. PDOs showed that the short course/high dose L-OHP scheme did not appear to be an effective choice for HIPEC in CRCPM. HIPEC administered under hyperthermia conditions enhanced the effect of chemotherapy drugs against cancer cells, affecting PDO viability and apoptosis. Finally, PDO co-cultured with cancer-associated fibroblast impacted HIPEC treatments by increasing PDO viability and reducing CASPASES activity., Conclusions: Our study suggests that PDOs could be a reliable in vitro model to evaluate HIPEC schemes at individual-patient level and to develop more effective treatment strategies for CRCPM., (© 2024. The Author(s).)