Hepatic Metastases Of Colorectal Cancer Research Articles

Hepatic Metastases of Colorectal Cancer: Therapeutic Strategy

Hepatic Metastases of Colorectal Cancer: Therapeutic Strategy

Influence of Biomarkers on Mortality among Patients with Hepatic Metastasis of Colorectal Cancer Treated with FOLFOX/CAPOX and FOLFIRI/CAPIRI, Including Anti-EGFR and Anti-VEGF Therapies.

Background and objectives: Colorectal cancer is a major global health concern, with a significant increase in morbidity and mortality rates associated with metastatic stages. This study investigates the prognostic significance of various clinical and laboratory parameters in patients with metastatic CRC. Materials and Methods: A retrospective cohort of 188 CRC patients with hepatic metastasis from the OncoHelp Association in Timisoara was analyzed from January 2016 to March 2023. Data on demographics, clinical characteristics, and biomarkers, such as lymphocyte counts, as well as various inflammation indices, were examined. Statistical analyses included univariate and multivariate logistic regression, Kaplan-Meier survival analysis, and ROC curve assessments. Results: Our findings indicate significant associations between survival outcomes and several biomarkers. Higher BMI and lymphocyte counts were linked with better survival rates, while higher values of Neutrophil-Hemoglobin-Lymphocyte (NHL) score, Neutrophil-Lymphocyte Ratio (NLR), Platelet-Lymphocyte Ratio (PLR), and Systemic Immune-Inflammation Index (SII) were predictors of poorer outcomes. Notably, the presence of hepatic metastasis at diagnosis was a critical factor, significantly reducing overall survival. Conclusions: The study has expanded the current understanding of prognostic factors in CRC, advocating for a multi-dimensional approach to prognostic evaluations. This approach should consider not only the traditional metrics such as tumor stage and histological grading but also incorporate a broader spectrum of biomarkers. Future studies should aim to validate these findings and explore the integration of these biomarkers into routine clinical practice, enhancing the precision of prognostic assessments and ultimately guiding more personalized treatment strategies for CRC patients.

NFKB2 mediates colorectal cancer cell immune escape and metastasis in a STAT2/PD‐L1‐dependent manner

This study systematically analyzed the molecular mechanism and function of nuclear factor kappa B subunit 2 (NFKB2) in colorectal cancer (CRC) to investigate the potential of NFKB2 as a therapeutic target for CRC. Various experimental techniques, including RNA sequencing, proteome chip assays, and small molecule analysis, were used to obtain a deeper understanding of the regulation of NFKB2 in CRC. The results revealed that NFKB2 was upregulated in a significant proportion of patients with advanced hepatic metastasis of CRC. NFKB2 played an important role in promoting tumor growth through CD8+ T-cell exhaustion. Moreover, NFKB2 directly interacted with signal transducer and activator of transcription 2 (STAT2), leading to increased phosphorylation of STAT2 and the upregulation of programmed death ligand 1 (PD-L1). Applying a small molecule inhibitor of NFKB2 (Rg5) led to a reduction in PD-L1 expression and improved response to programmed death-1 blockade-based immunotherapy. In conclusion, the facilitated NFKB2-STAT2/PD-L1 axis may suppress immune surveillance in CRC and targeting NFKB2 may enhance the efficacy of immunotherapeutic strategies. Our results provide novel insights into the molecular mechanisms underlying the contribution of NFKB2 in CRC immune escape.

The use of medical imaging methods for percutaneous radiofrequency ablation of hepatic metastases of colorectal cancer

The use of medical imaging methods for percutaneous radiofrequency ablation of hepatic metastases of colorectal cancer

The use of ablation technologies for the treatment of hepatic metastases of colorectal cancer

The use of ablation technologies for the treatment of hepatic metastases of colorectal cancer

INTRA-ARTERIAL CHEMOTHERAPY AS A CLINICAL OPTION FOR METASTATIC COLORECTAL CANCER: CONVERSION OF INOPERABLE LIVER METASTASES TO OPERABLE ILLUSTRATED WITH A CLINICAL CASE.

Colorectal cancer exerts a very high level of liver metastases, even on primary diagnosis, with 80%-90% unresectable nodules. At the same time, the possibility of resection has a significant impact on survival: 5-year survival is 6%-10% without liver surgery and up to 30% upon resection of liver metastases. Finding ways to improve resectability is a topical search for doctors all over the world. One of the promising methods to convert unresectable liver metastases of colorectal cancer into resectable ones is a hepatic artery infusion, or intra-arterial chemotherapy allowing for the delivery of cytotoxic drugs directly to the common hepatic artery via catheter or pump with decreased systemic toxicity and increased local drug concentration. In this article, we discuss the literature data on the impact of intra-arterial chemotherapy on the resectability of colorectal metastases in the liver and present the results of the successful clinical case. The literature shows a positive impact of the hepatic artery infusion on the resectability of hepatic metastases of colorectal cancer. The National Cancer Institute (Ukraine) has its own experience in hepatic artery infusion with further resection of primary-unresectable colorectal metastases in the liver. In our clinical case, a patient with liver-limited metastasis of colorectal cancer was initially inoperable due to the size of tumor lesions and an insufficient residual volume of the liver. Hepatic artery infusion tactics was chosen for this patient. The patient received six cycles of intra-arterial chemotherapy, namely five FOLFOX cycles and one 5-FU cycle, and then met the resectability criteria. Also, it is important to notice that the case demonstrates chemoresistance overcoming, since the patient had disease progression before, following systemically administered XELOX, and the period until readmission of the drugs was less than 6 months. So, hepatic artery infusion can be considered a promising method to convert unresectable liver metastases of colorectal cancer into resectable ones for highly selected patients.

Biliary Carcinoembryonic Antigen (CEA) Levels: The Role in Detection of Occult Hepatic Metastases in Colorectal Carcinoma

Objective: Colorectal carcinoma (CRC) is a major public health concern, often complicated by hepatic metastasis. Despite the widespread use of serum Carcinoembryonic Antigen (CEA) for postoperative monitoring, early detection of hepatic metastasis remains elusive. This study aims to evaluate the prognostic significance of CEA levels in both peripheral blood and gallbladder bile for predicting hepatic metastasis in CRC patients, and to explore its potential utility for personalized treatment regimens. Materials and Methods: A prospective randomized study was conducted over three years, enrolling 31 participants, 21 of whom underwent curative operations for CRC. Preoperative and postoperative CEA levels were assessed with rigorous diagnostic imaging and histological examinations. Patients were stratified into groups based on liver metastasis, postoperative chemotherapy, and CEA levels in both blood and bile. Results: A statistically significant difference was found in biliary CEA levels between patients with (mean = 129.22 ng/ml) and without intraoperative liver metastasis (mean = 33.16 ng/ml), p-value = 0.01. Serum and biliary CEA levels were robustly correlated, p > 0.05. Biliary CEA values differed significantly across Duke's stages, with particular significance between the control group and Duke's stage D (p < 0.001). Among patients without intraoperative liver metastasis but with biliary CEA >10 ng/ml, 80% developed liver metastasis postoperatively despite undergoing chemotherapy. Conclusion: This research highlights the pivotal role of biliary CEA levels in diagnosing latent hepatic metastases in colorectal cancer. Demonstrating superior sensitivity compared to traditional serum tests, biliary CEA presents a potential shift in early detection. Elevated levels suggest expanded therapeutic options, from timely hepatectomies to adopting radiofrequency ablation and anti-CEA monoclonal antibodies, enhancing the likelihood of better patient outcomes. Essentially, these findings enhance our understanding of colorectal cancer, emphasizing the importance of personalized care, early diagnosis, and customized treatments, thereby directing us toward better patient outcomes.

A Comprehensive Machine Learning Benchmark Study for Radiomics-Based Survival Analysis of CT Imaging Data in Patients With Hepatic Metastases of CRC.

Optimizing a machine learning (ML) pipeline for radiomics analysis involves numerous choices in data set composition, preprocessing, and model selection. Objective identification of the optimal setup is complicated by correlated features, interdependency structures, and a multitude of available ML algorithms. Therefore, we present a radiomics-based benchmarking framework to optimize a comprehensive ML pipeline for the prediction of overall survival. This study is conducted on an image set of patients with hepatic metastases of colorectal cancer, for which radiomics features of the whole liver and of metastases from computed tomography images were calculated. A mixed model approach was used to find the optimal pipeline configuration and to identify the added prognostic value of radiomics features. In this study, a large-scale ML benchmark pipeline consisting of preprocessing, feature selection, dimensionality reduction, hyperparameter optimization, and training of different models was developed for radiomics-based survival analysis. Portal-venous computed tomography imaging data from a previous prospective randomized trial evaluating radioembolization of liver metastases of colorectal cancer were quantitatively accessible through a radiomics approach. One thousand two hundred eighteen radiomics features of hepatic metastases and the whole liver were calculated, and 19 clinical parameters (age, sex, laboratory values, and treatment) were available for each patient. Three ML algorithms-a regression model with elastic net regularization (glmnet), a random survival forest (RSF), and a gradient tree-boosting technique (xgboost)-were evaluated for 5 combinations of clinical data, tumor radiomics, and whole-liver features. Hyperparameter optimization and model evaluation were optimized toward the performance metric integrated Brier score via nested cross-validation. To address dependency structures in the benchmark setup, a mixed-model approach was developed to compare ML and data configurations and to identify the best-performing model. Within our radiomics-based benchmark experiment, 60 ML pipeline variations were evaluated on clinical data and radiomics features from 491 patients. Descriptive analysis of the benchmark results showed a preference for RSF-based pipelines, especially for the combination of clinical data with radiomics features. This observation was supported by the quantitative analysis via a linear mixed model approach, computed to differentiate the effect of data sets and pipeline configurations on the resulting performance. This revealed the RSF pipelines to consistently perform similar or better than glmnet and xgboost. Further, for the RSF, there was no significantly better-performing pipeline composition regarding the sort of preprocessing or hyperparameter optimization. Our study introduces a benchmark framework for radiomics-based survival analysis, aimed at identifying the optimal settings with respect to different radiomics data sources and various ML pipeline variations, including preprocessing techniques and learning algorithms. A suitable analysis tool for the benchmark results is provided via a mixed model approach, which showed for our study on patients with intrahepatic liver metastases, that radiomics features captured the patients' clinical situation in a manner comparable to the provided information solely from clinical parameters. However, we did not observe a relevant additional prognostic value obtained by these radiomics features.

Targeting CDK12 obviates the malignant phenotypes of colorectal cancer through the Wnt/β-catenin signaling pathway

Colorectal cancer (CRC) is the second most common cause of cancer-related mortality and lies third in terms of morbidity due to the limited number of effective druggable targets. Since cancer stem cells (CSCs) are considered to be one of the roots of tumorigenesis, outgrowth and metastasis, targeting CSCs may be a promising strategy to reverse the malignant phenotypes of CRC. Cyclin-dependent kinase 12 (CDK12) has been reported to be involved in the self-renewal of CSCs in various cancers, rendering it an attractive potential target against CSCs to consequently limit the malignant phenotypes in CRC. In the present study, we aimed to investigate whether CDK12 can be a potential therapeutic target for patients with CRC and clarify its underlying mechanism. We found that CDK12, but not CDK13 is required for CRC survival. CDK12 was found to drive tumor initiation according to the colitis-associated colorectal cancer mouse model. In addition, CDK12 promoted CRC outgrowth and hepatic metastasis in the subcutaneous allograft and liver metastasis mouse models, respectively. In particular, CDK12 was able to induce the self-renewal of CRC CSCs. Mechanistically, the activation of Wnt/β-catenin signaling mediated by CDK12 was implicated in stemness regulation and malignant phenotype maintenance. These findings indicate that CDK12 is a candidate druggable target in CRC. Therefore, the CDK12 inhibitor SR-4835 warrants clinical trial testing in patients with CRC.

MiR-152–3p facilitates cell adhesion and hepatic metastases in colorectal cancer via targeting AQP11

BackgroundTumor metastasis is a fundamental reason for the poor prognosis of colorectal cancer (CRC) patients. Publications suggested that upregulated Aquaporin-11 (AQP11) can improve CRC patients’ prognoses, but few articles investigated the regulation of AQP11 in CRC cell adhesion and hepatic metastases. Therefore, this study will explore the regulatory mechanism of AQP11 regulating CRC cell adhesion and hepatic metastases at the molecular level. MethodsAQP11 and miR-152–3p expression were analyzed based on The Cancer Genome Atlas-Colon Adenocarcinoma/Rectum Adenocarcinoma (TCGA-COAD/READ) dataset and several other datasets. The upstream genes of AQP11 were predicted via StarBase and MicroRNA Data Integration Portal (mirDIP) databases. The signaling pathways in which the downregulated AQP11 enriched were analyzed via Gene Set Enrichment Analysis (GSEA). Cell proliferation, migration, invasion, and adhesion were respectively tested via western blot, Transwell, and cell adhesion assays. The expression of adhesion-related proteins was determined via enzyme-linked immunosorbent assay (ELISA). AQP11 protein level was examined via western blot, and AQP11 functions were validated via nude mice xenograft experiment. ResultsAQP11 was downregulated in CRC, and the upregulated AQP11 remarkably repressed cell proliferation, migration, invasion, and adhesion. The silenced AQP11 notably facilitated the above cell functions in CRC. In addition, AQP11 was negatively regulated by miR-152–3p. In vitro cellular assays revealed that miR-152–3p, by targeting AQP11, facilitated CRC cell proliferation, migration, invasion, and adhesion. An in vivo assay suggested that AQP11 could notably repress CRC growth and metastasis. ConclusionThe above results confirmed that miR-152–3p/AQP11 axis could regulate CRC hepatic metastases and would be a promising target in anti-cancer treatment.

Radiofrequency ablation in treatment of hepatic metastases of colorectal cancer

Radiofrequency ablation in treatment of hepatic metastases of colorectal cancer

Intra-arterial hepatic bevacizumab and systemic chemotherapy in hepatic metastasis of colorectal cancer: A phase II multicentric trial in second-line treatment

IntroductionIntra-arterial hepatic (IAH) treatment has shown promising results in the management of patients with unresectable colorectal liver metastases (CRLM) the prognosis of which is poor. Bevacizumab adjunction to standard chemotherapy has been shown to improve survival of this patient population. This prospective study was conducted to assess the efficacy and safety of IAH bevacizumab combined to systemic chemotherapy after first-line treatment failure in patients with CRLM. MethodsIncluded patients had dominant or isolated unresectable CRLM progressing after standard first-line treatment for metastases of colorectal cancer. Three patients had less than 30% liver invasion, three patients between 30 and 50%, two more than 50% and data was missing in two patients. An intra-hepatic catheter was implanted surgically or percutaneously. Bevacizumab 7.5 mg/kg was administered once every 3 weeks in combination with capecitabine 2000 mg/m² per day for 2 weeks and oxaliplatin 130 mg/m² or irinotecan 200 mg/m² once every 3 weeks. The primary end-point was the objective response rate. ResultsBetween June 2013 and February 2015, 10 patients were included. The trial was prematurely closed because of the lack of financial support and poor accrual. The patients had a median of 6 [1–9] cycles of treatment. Partial response was achieved in 2 patients (20%) and a R0 liver metastases resection in one another. All patients died of disease progression. The median overall and progression-free survival rates were respectively 14.0 (95% IC [4.8 – 25.8] and 5.4 months (95% IC [1.6 – 6.2]). Four patients had severe side effects but no toxic death occurred. ConclusionIAH bevacizumab combined to systemic chemotherapy is feasible and safe in patients with unresectable isolated or dominant CRLM progressing after a first-line systemic treatment. Based on the low number of patients included in our study, our results suggest that this treatment does not increase dramatically the response rate versus an adapted systemic treatment. However, considering the safety data provided in this study, arterial infusion of bevacizumab in adjunction to chemotherapeutic agents could be evaluated in the future.

CDK12 orchestrates super-enhancer-associated CCDC137 transcription to direct hepatic metastasis in colorectal cancer.

BackgroundHepatic metastasis is the primary and direct cause of death in individuals with colorectal cancer (CRC) attribute to lack of effective therapeutic targets. The present study aimed to identify potential druggable candidate targets for patients with liver metastatic CRC.MethodsThe transcriptional profiles of super‐enhancers (SEs) in primary and liver metastatic CRC were evaluated in publicly accessible CRC datasets. Immunohistochemistry of human CRC tissues was conducted to determine the expression level of CDK12. Cellular proliferation, survival and stemness were examined upon CDK12 inhibition by shCDK12 or a selective CDK12 inhibitor named SR‐4835 with multiple in vitro and in vivo assays. RNA sequencing and bioinformatics analyses were carried out to investigate the mechanisms of CDK12 inhibition in CRC cells.ResultsWe identified CDK12 as a driver gene for direct hepatic metastasis in CRC. Suppression of CDK12 led to robust inhibition of proliferation, survival and stemness. Mechanistically, CDK12 intervention preferentially repressed the transcription of SE‐associated genes. Integration of the SE landscape and RNA sequencing, BCL2L1 and CCDC137 were identified as SE‐associated oncogenic genes to strengthen the abilities of cellular survival, proliferation and stemness, eventually increasing liver metastasis of CRC.ConclusionsOur data highlight the potential of CDK12 and SE‐associated oncogenic transcripts as therapeutic targets for patients with liver metastatic CRC.

The Role of Inflammatory Mediators in Colorectal Cancer Hepatic Metastasis.

Colorectal cancer (CRC) is the second leading cause of death in cancer patients in the USA, whereas the major cause of CRC deaths is hepatic metastases. The liver is the most common site of metastasis in patients with CRC due to hepatic portal veins receiving blood from the digestive tract. Understanding the cellular and molecular mechanisms of hepatic metastases is of dire need for the development of potent targeted therapeutics. Immuno-signaling molecules including cytokines and chemokines play a pivotal role in hepatic metastases from CRC. This brief review discusses the involvement of three representative cytokines (TNF-α, IL-6 and IL-1β), a lipid molecule PGE2 and two chemokines (CXCL1 and CXCL2) in the process of CRC liver metastases.

High-Fat Diet Enhances the Liver Metastasis Potential of Colorectal Cancer through Microbiota Dysbiosis.

Simple SummaryHigh-fat diet (HFD) is hypothesized to induce gut dysbiosis and promote colorectal cancer (CRC). However, the specific mechanisms involved require investigation. In this study, we established an animal model and utilized 16S sequencing to determine the effects of HFD on gut microbiota, as well as on the colon and liver. Furthermore, due to the abundance of Desulfovibrio (DSV) in the faecal samples of HFD-fed rats and CRC hepatic metastasis patients, we also conducted a DSV gavage animal experiment to determine the role of DSV in CRC development. Our study confirmed that HFD could cause microbiota dysbiosis, especially DSV enrichment, and may promote CRC initiation and metastasis.Obesity, metabolic changes, and intestinal microbiota disruption significantly affect tumorigenesis and metastasis in colorectal cancer (CRC). However, the relationships among these factors remain poorly understood. In this study, we found that a high-fat diet (HFD) promoted gut barrier dysfunction and inflammation in the colorectum and liver. We further investigated gut microbiota changes through 16S rRNA sequencing of faecal samples from HFD-fed rats and CRC hepatic metastasis patients and found an abundance of Desulfovibrio (DSV). DSV could also induce barrier dysfunction in the colorectum and inflammation in the colorectum and liver, suggesting that it contributes to the formation of a microenvironment conducive to CRC tumorigenesis and metastasis. These findings highlight that HFD-induced microbiota dysbiosis, especially DSV abundance, could promote CRC initiation and metastasis.

Clinical evolution after surgery of hepatic metastases of colorectal cancer according to genomic profile.

188 Background: Hepatic metastatic disease from colorectal cancer (CRC) is a significant clinical problem, as the liver is the dominant metastatic site for patients with CRC and 25% of patients will have liver affection at diagnosis. Due to improvement in systemic therapy and locoregional treatments in the last decade, survival has increased significantly. In this regard, it is key to be able to establish several prognostic factors that significantly influence survival. Methods: We carried out a retrospective analysis of 554 patients with mCRC treated at the Gregorio Marañon Hospital (Madrid, Spain) between January 2010 and 2021. We analyzed the clinical and molecular characteristics of patients undergoing liver metastasis surgery as first metastasis surgery together with relapse patterns to progression. Results: Out of our cohort of 554 patients with mCRC we identified 169 patients that underwent liver metastasis surgery as 1st surgery, achieving a media of survival of 56.38 months [95% CI, 44.21-73.78 months]. Regarding the clinical characteristics of the population, the majority were men (63,91%) and had a PS 0-1 (90,5%); and 46 patients (27,2%) were more than 70 years old. In relation to the location of the primary tumour, 46 patients (27,2%) had it n the right colon and 120 in the left colon (71,0%). And 43 patients (25,4%) had extrahepatic disease at the time of surgery. Regarding the biomakers, we indentified the following mutations: 68 mutated KRAS (40,2%), 5 mutated NRAS (2,9%), 9 mutated BRAF (5,3%), 13 mutated PI3K (7,6%), 1 HER2 amplification (0,5%) and 4 with IMS phenotype (2,3%). After the metastasis surgery, progression was mainly hepatic (50,3%), followed by pulmonary (24,8%), peritoneal (11,8%), lymph node (12%), bones (4,7%) and cerebral (1,1%), without having significant differences in relapse patterns at the statistics when analyzed by genomic profile. When analyzing progression-free survival (PFS) and overall survival (OS) according to the genomic profile, in the BRAF mutated vs BRAF WT population, no statistically significant differences were found, obtaining therefore an evident benefit. Furthermore, we found significant differences in OS for patients with right vs left primary tumour as well as for patients with extrahepatic involvement at the time of surgery. Conclusions: Patients undergoing sequential metastatic surgery have a long survival, so it is important to analyse patterns of relapse and clinical course. There is no evidence of significant differences in the progression patterns according to the mutational status of the mCRC; but selected patients with BRAF mutations may obtain benefit in PFS and OS with locoregional approaches to their liver disease.

Using texture analysis in the development of a potential radiomic signature for early identification of hepatic metastasis in colorectal cancer

BackgroundRadiomics allows information not readily available to the naked eye to be extracted from high resolution imaging modalities such as CT. Identifying that a cancer has already metastasised at the time of presentation through a radiomic signature will affect the treatment pathway. The ability to recognise the existence of metastases earlier will have a significant impact on the survival outcomes. AimTo create a novel radiomic signature using textural analysis in the evaluation of synchronous liver metastases in colorectal cancer. MethodsCT images at baseline and subsequent surveillance over a 5-year period of patients with colorectal cancer were processed using textural analysis software. Comparison was made between those patients who developed liver metastases and those that remained disease free to detect differences in the ‘texture’ of the liver. ResultsA total of 24 patients were divided into two matched groups for comparison. Significant differences between the two groups scores when using the textural analysis programme were found on coarse filtration (p = 0.044). Patients that went on to develop metastases an average of 18 months after presentation had higher levels of hepatic heterogeneity on CT. ConclusionThis initial study demonstrates the potential of using a textural analysis programme to build a radiomic signature to predict the development of hepatic metastases in rectal cancer patients otherwise thought to have clear staging CT scans at time of presentation.

TCF4 enhances hepatic metastasis of colorectal cancer by regulating tumor-associated macrophage via CCL2/CCR2 signaling

Colorectal cancer (CRC) liver metastasis is a significant clinical problem for which better therapies are urgently needed. Tumor-associated macrophage, a major cell population in the tumor microenvironment, is a known contributor to primary cancer progression and cancer metastasis. Here, we found TAM recruitment and M2 polarization were increased in the hepatic metastatic lesion compared with the primary site of human CRC tissues. Moreover, Pearson correlation analysis showed that TAM recruitment and polarization were closely correlated with the elevated TCF4 expression in the metastatic site. To investigate the role of TCF4 in CRC liver metastasis, we generated a syngeneic mouse model using MC38 cells splenic injection. Results from in vivo experiments and mouse models revealed that TCF4 deficiency in MC38 cells does not affect their proliferation and invasion; however, it reduces TAM infiltration and M2 polarization in the metastasis site. Further studies indicated that these effects are mediated by the TCF4 regulated CCL2 and CCR2 expression. TCF4 or CCL2 silencing in the tumor cells prevent CRC liver metastasis in the mouse model. Altogether, these findings suggest that the TCF4-CCL2-CCR2 axis plays an essential role in CRC liver metastasis by enhancing TAMs recruitment and M2 polarization.

Portal Vein Injection of Colorectal Cancer Organoids to Study the Liver Metastasis Stroma.

Hepatic metastasis of colorectal cancer (CRC) is a leading cause of cancer-related death. Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment, play a crucial role in metastatic CRC progression and predict poor patient prognosis. However, there is a lack of satisfactory mouse models to study the crosstalk between metastatic cancer cells and CAFs. Here, we present a method to investigate how liver metastasis progression is regulated by the metastatic niche and possibly could be restrained by stroma-directed therapy. Portal vein injection of CRC organoids generated a desmoplastic reaction, which faithfully recapitulated the fibroblast-rich histology of human CRC liver metastases. This model was tissue-specific with a higher tumor burden in the liver when compared to an intra-splenic injection model, simplifying mouse survival analyses. By injecting luciferase-expressing tumor organoids, tumor growth kinetics could be monitored by in vivo imaging. Moreover, this preclinical model provides a useful platform to assess the efficacy of therapeutics targeting the tumor mesenchyme. We describe methods to examine whether adeno-associated virus-mediated delivery of a tumor-inhibiting stromal gene to hepatocytes could remodel the tumor microenvironment and improve mouse survival. This approach enables the development and assessment of novel therapeutic strategies to inhibit hepatic metastasis of CRC.

Portal Vein Injection of Colorectal Cancer Organoids to Study the Liver Metastasis Stroma

Hepatic metastasis of colorectal cancer (CRC) is a leading cause of cancer-related death. Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment, play a crucial role in metastatic CRC progression and predict poor patient prognosis. However, there is a lack of satisfactory mouse models to study the crosstalk between metastatic cancer cells and CAFs. Here, we present a method to investigate how liver metastasis progression is regulated by the metastatic niche and possibly could be restrained by stroma-directed therapy. Portal vein injection of CRC organoids generated a desmoplastic reaction, which faithfully recapitulated the fibroblast-rich histology of human CRC liver metastases. This model was tissue-specific with a higher tumor burden in the liver when compared to an intra-splenic injection model, simplifying mouse survival analyses. By injecting luciferase-expressing tumor organoids, tumor growth kinetics could be monitored by in vivo imaging. Moreover, this preclinical model provides a useful platform to assess the efficacy of therapeutics targeting the tumor mesenchyme. We describe methods to examine whether adeno-associated virus-mediated delivery of a tumor-inhibiting stromal gene to hepatocytes could remodel the tumor microenvironment and improve mouse survival. This approach enables the development and assessment of novel therapeutic strategies to inhibit hepatic metastasis of CRC.