Treatment Of Colorectal Cancer Liver Metastases Research Articles

Exosomal miR-106a-5p from highly metastatic colorectal cancer cells drives liver metastasis by inducing macrophage M2 polarization in the tumor microenvironment

BackgroundThe tumor microenvironment (TME) is a dynamic system orchestrated by intricate cell-to-cell crosstalk. Specifically, macrophages within the TME play a crucial role in driving tumor progression. Exosomes are key mediators of communication between tumor cells and the TME. However, the mechanisms underlying exosome-driven crosstalk between tumor cells and macrophages during colorectal cancer (CRC) progression remain incompletely elucidated.MethodsSingle-cell RNA sequencing were analyzed using the Seurat package. Exosomes were isolated using ultracentrifugation and characterized by transmission electron microscopy, nanoparticle tracking analysis, and western blot. miRNAs differentially expressed in exosomes were analyzed using the limma package. CD206 expression in CRC tissues, exosomes tracing, and exosomal miR-106a-5p transport were observed through immunofluorescence. Macrophage polarization was assessed via qRT-PCR, ELISA, and flow cytometry. The interactions between miR-106a-5p, hnRNPA1, and SOCS6 were evaluated using miRNA pull-down, RIP, and dual-luciferase reporter assays. Transwell assays and liver metastasis model explored the role of exosomal miR-106a-5p-induced M2 macrophages in promoting CRC liver metastasis.ResultThe proportion of M2 macrophages is increased in CRC with liver metastasis compared to those without. Highly metastatic CRC cells release exosomes enriched with miR-106a-5p, which promote macrophages M2 polarization by suppressing SOCS6 and activating JAK2/STAT3 pathway. These M2 macrophages reciprocally enhance CRC liver metastasis. hnRNPA1 regulate the transport of miR-106a-5p into exosomes. Clinically, elevated miR-106a-5p in plasma exosomes correlated with liver metastasis and poor prognosis.ConclusionCRC-derived exosomal miR-106a-5p plays a critical role in promoting liver metastasis and is a potential biomarker for the prevention and treatment of CRC liver metastasis.

MiR-455/GREM1 axis promotes colorectal cancer progression and liver metastasis by affecting PI3K/AKT pathway and inducing M2 macrophage polarization

BackgroundColorectal cancer is among the most common malignant tumors affecting the gastrointestinal tract. Liver metastases, a complication present in approximately 50% of colorectal cancer patients, are a considerable concern. Recently, studies have revealed the crucial role of miR-455 in tumor pathogenesis. However, the effect of miR-455 on the progression of liver metastases in colorectal cancer remains controversial. As an antagonist of bone morphogenetic protein(BMP), Gremlin 1 (GREM1) may impact organogenesis, body patterning, and tissue differentiation. Nevertheless, the role of miR-455 in regulating GREM1 in colorectal cancer liver metastases and how miR-455/GREM1 axis influences tumour immune microenvironment is unclear.MethodsBioinformatics analysis shows that miR-455/GREM1 axis plays crucial role in liver metastasis of intestinal cancer and predicts its possible mechanism. To investigate the impact of miR-455/GREM1 axis on the proliferation, invasion, and migration of colorectal cancer cells, colony formation assay, wound healing and transwell assay were examined in vitro. The Dual-Luciferase reporter gene assay and RNA pull-down assay confirmed a possible regulatory effect between miR-455 and GREM1. In vivo, colorectal cancer liver metastasis(CRLM) model mice was established to inquiry the effect of miR-455/GREM1 axis on tumor growth and macrophage polarization. The marker of macrophage polarization was tested using immunofluorescence(IF) and quantitative real-time polymerase chain reaction(qRT-PCR). By enzyme-linked immunosorbent assay (ELISA), cytokines were detected in culture medium supernatants.ResultsWe found that miR-455 and BMP6 expression was increased and GREM1 expression was decreased in liver metastase compared with primary tumor. miR-455/GREM1 axis promotes colorectal cancer cells proliferation, migration, invasion via affected PI3K/AKT pathway. Moreover, downregulating GREM1 augmented BMP6 expression in MC38 cell lines, inducing M2 polarization of macrophages, and promoting liver metastasis growth in CRLM model mice.ConclusionThese data suggest that miR-455/GREM1 axis promotes colorectal cancer progression and liver metastasis by affecting PI3K/AKT pathway and inducing M2 macrophage polarization. These results offer valuable insights and direction for future research and treatment of CRLM.

An evaluation model of hepatic steatosis based on CT value and serum uric acid/HDL cholesterol ratio can predict intrahepatic recurrence of colorectal cancer liver metastasis.

Intrahepatic recurrence is one of the main causes of treatment failure in patients with colorectal cancer liver metastasis (CRLM). Hepatic steatosis was reported to provide fertile soil for metastasis. The effect of irinotecan-inducted hepatic steatosis on the progression of liver metastasis remains to be verified. Therefore, we aim to clarify the effect of hepatic steatosis on postoperative intrahepatic recurrence in CRLM and whether it is relevant to irinotecan-based chemotherapy. Data for a total of 284 patients undergoing curative surgical treatment for CRLMs were retrospectively reviewed between March 2007 and June 2018. Hepatic steatosis score (HSS) was established by combining Liver to Spleen CT ratio (LSR) and Uric acid to HDL-cholesterol ratio (UHR) to detect the presence of hepatic steatosis. The evaluation model is consistent with pathological results and has high prediction ability and clinical application value. Patients with HSS high risk (HSS-HR) had significantly worse prognosis than those with HSS low risk (HSS-LR) (3-year intrahepatic RFS: 42.7% vs. 29.4%, P = 0.003; 5-year OS: 45.7% vs. 26.5%, P = 0.002). Univariate and multivariate analysis confirmed its essential role in the prediction of intrahepatic RFS. Besides, patients treated with preoperative irinotecan chemotherapy were more likely to end up with HSS-HR than those with non-irinotecan chemotherapy (63.3% vs. 21.8%, P < 0.001). Furthermore, irinotecan chemotherapy is relevant to worse prognosis in baseline HSS-HR patients. In summary, patients with HSS-HR had significantly worse 5-year OS and 3-year intrahepatic RFS. Irinotecan chemotherapy is more likely to lead to HSS-HR and pre-existing hepatic steatosis may be a worse prognostic factor limiting patients underwent IRI-based chemotherapy.

Malnutrition as an unfavorable prognostic factor after surgical treatment for metastatic colorectal cancer.

&lt;b&gt;&lt;br&gt;Introduction:&lt;/b&gt; Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths worldwide. Distant metastases are usually located in the liver and are present in 50% of patients.&lt;/br&gt; &lt;b&gt;&lt;br&gt;Aim:&lt;/b&gt; The aim of this study is to evaluate changes in body composition and phase angle before and after surgical treatment of CRC liver metastases, as well as survival time and treatment costs.&lt;/br&gt; &lt;b&gt;&lt;br&gt;Material and methods:&lt;/b&gt; The study included 134 patients who received 174 surgeries for CRC liver metastases. Bioelectrical impedance analysis (BIA) was performed using an AKERN BIA 101 analyzer.&lt;/br&gt; &lt;b&gt;&lt;br&gt;Results:&lt;/b&gt; BIA was performed before and after surgery. The results of tests (total body water content [TBW], body cell mass [BCM], and phase angle) showed a reduction in BCM by 2.21 kg and a statistically significant decrease in phase angle values after surgery (from 5.06 to 4.25 in women and from 5.34 to 4.76 in men). These values are below the reference range for both sexes. There was a correlation between phase angle values and muscle mass, both before (R = 0.528, p&lt;0001) and after surgery (R = 0.634, p&lt;000.1). Preoperative levels of the tumor marker CEA were elevated in more than half of the patients. The median survival time after resection of liver metastases was 37.6 months.&lt;/br&gt; &lt;b&gt;&lt;br&gt;Discussion:&lt;/b&gt; A significant factor that increases complications, mortality, and treatment costs of cancer patients is malnutrition, which could be the earliest symptom of malignant disease.&lt;/br&gt; &lt;b&gt;&lt;br&gt;Conclusions:&lt;/b&gt; Successful treatment of CRC requires the patients to participate in follow-up examinations and to be aware of early signs associated with recurrence (e.g., blood in the stool or weight loss). The patients' nutritional status should be monitored and recorded in a DILO card.&lt;/br&gt.

Multimodal Management of Colorectal Liver Metastases: State of the Art.

Liver is the most common site of colorectal cancer (CRC) metastases. Treatment of CRC liver metastases (CRLM) includes different strategies, prevalently based on the clinical and oncological intent. Valid approaches in liver-limited or liver-prevalent disease include surgery, percutaneous ablative procedures (radiofrequency ablation, microwave ablation), intra-arterial perfusional techniques (chemo-embolization, radio-embolization) as well as stereotactic radiotherapy. Systemic treatments, including chemotherapy, immunotherapy and other biological agents, are the only options for patients with no chance of locoregional approaches. The use of chemotherapy in other settings, such as neoadjuvant, adjuvant or conversion therapy of CRLM, is commonly accepted in the clinical practice, although data from several clinical trials have been mostly inconclusive. The optimal integration of all these strategies, when applicable and clinically indicated, should be ever considered in patients affected by CRLM based on clinical evidence and multidisciplinary experience. Here we revised in detail all the possible therapeutic approaches of CRLM focusing on the current evidences, the studies still in progress and the often contradictory data.

Microbiota in colorectal cancer related to liver metastasis.

The prevalence of colorectal cancer (CRC) is increasing annually and metastasis is the principal cause of death in patients with CRC, with the liver being the most frequently affected site. Many studies have shown a strong interplay between the gut flora, particularly Fusobacterium nucleatum (F. nucleatum), Escherichia coli, and Bacteroides fragilis, and the development of gut tumors. Some strains can induce gut inflammation and produce toxins that directly harm gut epithelial cells, ultimately accelerating the onset and progression of CRC. However, little clinical evidence exists on the specific interplay between the gut microflora and colorectal cancer liver metastasis (CRLM). Some research showed the existence of viable F. nucleatum in distant metastasis of CRC. Subsequently, gut microbiota products, such as lipopolysaccharides, sodium butyrate, and protein cathepsin K, were also found to affect the development of CRC. This article summarizes the mechanism and research status of the interplay between gut microflora and CRLM, discusses the importance of gut microflora in the treatment of CRLM, and proposes a new approach to understanding the mechanism of CRLM and potential treatments for the microbiome. It is anticipated that the gut microbiota will be a formidable therapeutic and prophylactic tool for treating and preventing CRLM.

Colorectal Cancer Liver Metastasis—State-of-the-Art and Future Perspectives

The current management of colorectal cancer liver metastasis (CRCLM) patients involves a multidisciplinary approach, with surgical resection remaining the primary curative option. The advances in liver surgery have improved outcomes, enabling more patients to undergo surgery successfully. In addition, the development of imaging software has improved the preoperative planning and patient selection for surgery and other interventions. Systemic therapies, such as targeted therapies and immunotherapies, have enhanced the chances of complete resection. Targeted agents, in combination with chemotherapy, have shown efficacy in downstaging tumors and increasing resectability. The algorithm approach for these patients continues to evolve, driven by a deeper understanding of the underlying biology. Personalized medicine, guided by molecular profiling and the potential of liquid biopsies in this field, may lead to more tailored treatment strategies. A greater understanding of the immune microenvironment in CRLM may unlock the potential for immune checkpoint inhibitors and novel immunotherapies to become more prominent in the treatment landscape. This review explores the current state-of-the-art treatment of CRCLM and discusses promising future perspectives.

Colorectal cancer hepatic metastases resection margins outcomes: a single-centre retrospective cohort study.

Surgical resection is the most efficient treatment for isolated colorectal cancer hepatic metastases. Among the known prognostic factors of this procedure, the impact of the resection margin width is still a controversial matter in the literature. A retrospective cohort study was performed including 170 patients who underwent surgical resection of colorectal cancer liver metastases (CRLMs) between 2006 and 2016 in our hepatobiliary unit. Resection margin width was determined histologically by measuring the distance from the tumour in millimetres or centimetres. Patients' clinical characteristics were also collected. Patients were then stratified in two tumour margin groups: below 5mm (group A) and equal to or above 5mm (group B). Overall survival (OS) and disease-free survival (DFS) were the primary outcomes. Kaplan-Meier curves showed significantly better outcomes for cases having resection margins above 5mm for both DFS with 1508.7 days (range 1151.2-1866.2) in group A, compared to 2463.9 days (range 2021.3-2906.5) in group B (P=0.049), and OS with 1557.8 days (range 1276.3-1839.3) for group A and 2303.8 days (range 1921.2--2686.4) for group B (P=0.020). This survival benefit was not significant for patients presenting with stage IV CRC at diagnosis or cases where extended (7+ segments) resections were performed. Five-millimetre margins provide a significant survival advantage and should be aimed for in the treatment of CRLMs. Further research on the cause for this finding, including tumour biology's impact on survival, is required.

CHSY1 promotes CD8+ T cell exhaustion through activation of succinate metabolism pathway leading to colorectal cancer liver metastasis based on CRISPR/Cas9 screening

BackgroundThe most common site of metastasis in colorectal cancer (CRC) is the liver and liver metastases occur in more than 50% of patients during diagnosis or treatment. The occurrence of metastasis depends on a series of events known as the invasive-metastasis cascade. Currently, the underlying genes and pathways regulating metastasis initiation in the liver microenvironment are unknown.MethodsWe performed systematic CRISPR/Cas9 screening using an in vivo mouse model of CRC liver metastasis to identify key regulators of CRC metastasis. We present the full results of this screen,which included a list of genes that promote or repress CRC liver colonization. By silencing these genes individually, we found that chondroitin sulfate synthase 1 (CHSY1) may be involved in CRC metastasis. We verified the function of CHSY1 and its involvement in liver metastasis of CRC through in vivo and in vitro experiments.ResultThe results of TCGA and CRISPR/Cas9 showed that CHSY1 was overexpressed in CRC primary and liver metastasis tissues and indicated a worse clinical prognosis. In vitro and in vivo experiments confirmed that CHSY1 facilitated the liver metastasis of CRC and CHSY1 induced CD8+ T cell exhaustion and upregulated PD-L1 expression. The metabolomic analysis indicated that CHSY1 promoted CD8+ T cell exhaustion by activating the succinate metabolism pathway leading to liver metastasis of CRC. Artemisinin as a CHSY1 inhibitor reduced liver metastasis and enhanced the effect of anti-PD1 in CRC. PLGA-loaded Artemisinin and ICG probe reduced liver metastasis and increased the efficiency of anti-PD1 treatment in CRC.ConclusionCHSY1 could promote CD8+ T cell exhaustion through activation of the succinate metabolic and PI3K/AKT/HIF1A pathway, leading to CRC liver metastasis. The combination of CHSY1 knockdown and anti-PD1 contributes to synergistic resistance to CRC liver metastasis. Artemisinin significantly inhibits CHSY1 activity and in combination with anti-PD1 could synergistically treat CRC liver metastases. This study provides new targets and specific strategies for the treatment of CRC liver metastases, bringing new hope and benefits to patients.

Intraoperative Ultrasound in Colorectal Liver Metastases

Intraoperative ultrasound (IOUS) is a diagnostic technique that allows obtaining additional information about the number and localization of colorectal cancer (CRC) metastases in the liver (especially with their intraparenchymal location), determining their relationship with the arteries and veins of the liver, navigating for puncture biopsy and / or performing minimally invasive treatment of lesions, and adjusting the amount of resection intervention on the liver during surgery. When performing minimally invasive medical procedures, IOUS application helps to avoid injuries to blood vessels, bile ducts and adjacent organs, and also allows evaluating the effectiveness of treatment and identifying potential complications. An important component of IOUS is the support of surgical procedures with a staged assessment of the liver hemodynamics, providing an immediate correction of the surgical situation. Thus, IOUS is a safe, inexpensive and highly informative diagnostic option, which should be a mandatory diagnostic step in the surgical treatment of CRC liver metastases.Based on literature data and personal experience, the authors present indications, technical aspects and features of application of various IOUS options and modalities in the surgical treatment of CRC liver metastases.

Perspectives of patients with colorectal cancer liver metastases on e-consultation in transmural care: a qualitative study

BackgroundComprehensive cancer networks have been established to deliver high-quality care for patients with cancer. Logistic challenges are faced, when patients need to be referred for specialized treatments. Despite strengthened privacy legislations, digital platforms are increasingly used to consult specialists from dedicated liver centers or refer patients with colorectal cancer liver metastases (CRLM) for local treatment strategies. This qualitative study aimed to explore the perspectives of patients with CRLM regarding e-consultation of transmural specialists.MethodsA focus group study was conducted. Patients referred from regional hospitals to an academic liver center for treatment of CRLM were asked to participate. Focus group discussions were audio-recorded and transcribed verbatim. A thematic content analysis of data was conducted, comprising open, axial, and selective coding of the transcripts. The consolidated criteria for reporting qualitative research (COREQ) were used.ResultsTwo focus groups were held, involving 11 patients and 8 relatives. Three major themes were identified with regard to e-consultation in transmural care: ‘data management’, ‘expertise’, and ‘information and coordination’. Confidence in the expertise of physicians appeared most important during the course of treatment, as patients experienced uncertainty after diagnosis of cancer. Despite the privacy risks, use of digital communication platforms to contact experts in the field were strongly endorsed to improve eligibility for potentially curative treatment. Moreover, e-consultation of specialists may reduce waiting times, due to effective coordination of care.ConclusionInitiatives to improve medical data transfer between care providers were encouraged to achieve effective coordination of oncological care. The potential hazard of privacy violation associated with digital data exchange is accepted by patients and their relatives, provided that use of digital data improves patient’s own health care, research or education.

Extracellular vesicles from colorectal cancer cells promote metastasis via the NOD1 signalling pathway.

Pattern‐recognition receptors (PRRs) have been shown to promote tumour metastasis via sensing tumour cell‐derived small extracellular vesicles (EVs). Nucleotide‐binding oligomerisation domain 1 (NOD1), a cytoplasmic PRR, plays a role in colorectal cancer (CRC) by detecting bacterial products. However, the precise mechanisms underlying the effects of NOD1, following identification of CRC cell‐derived EVs (CRC‐EVs), to potentiate CRC liver metastasis (CRC‐LM), remain poorly understood. Here, we demonstrate that CRC‐EVs activate NOD1 in macrophages to initiate secretion of inflammatory cytokines and chemokines. NOD1‐activated macrophages also promote CRC cell migration, while in a murine model of liver metastasis (LM), NOD1‐deficient mice exhibit reduced metastasis following CRC‐EV treatment. Furthermore, cell division cycle 42 (CDC42), a small Rho guanosine‐5′‐triphosphate (GTP)ase, is delivered by CRC‐EVs into macrophages where it activates NOD1. In addition, EVs from the plasma of patients with CRC‐LM mediate NOD1 activation in human peripheral blood mononuclear cells. Moreover, high NOD1 expression in tumour tissues is associated with poor prognosis of CRC‐LM. Our findings suggest that CRC‐EVs activate NOD1 to promote tumour metastasis, thus, NOD1 may serve as a potential target in the diagnosis and treatment of CRC‐LM.

Limited Effect of Perioperative Systemic Therapy in Patients Selected for Repeat Local Treatment of Recurrent Colorectal Cancer Liver Metastases.

The aim of this study was to determine the potential benefit of perioperative systemic therapy on overall and progression-free survival after repeat local treatment in patients suffering from recurrent colorectal cancer liver metastasis (CRLM). The optimal treatment strategy in patients with recurrent CRLM needs to be clarified, in particular for those suffering from early recurrence of CRLM. In this multicenter observational cohort study, consecutive patients diagnosed with recurrent CRLM between 2009 and 2019 were retrospectively identified in 4 academic liver surgery centers. Disease-free interval after initial local treatment of CRLM was categorized into recurrence within 6, between 6 and 12, and after 12 months. Perioperative systemic therapy consisted of induction, (neo)adjuvant, or combined regimens. Overall and progression-free survival after repeat local treatment of CRLM were analyzed by multivariable Cox regression analyses, resulting in adjusted hazard ratios (aHRs). Out of 303 patients included for analysis, 90 patients received perioperative systemic therapy for recurrent CRLM. Favorable overall (aHR, 0.45; 95% confidence interval [CI], 0.26-0.75) and progression-free (aHR, 0.53; 95% CI, 0.35-0.78) survival were observed in patients with a disease-free interval of more than 12 months. No significant difference in overall and progression-free survival was observed in patients receiving perioperative systemic therapy at repeat local treatment of CRLM, stratified for disease-free interval, previous exposure to chemotherapy, and RAS mutation status. No benefit of perioperative systemic therapy was observed in overall and progression-free survival after repeat local treatment of recurrent CRLM.

Small Interfering RNA in Colorectal Cancer Liver Metastasis Therapy.

Colorectal cancer (CRC) is associated with numerous genetic disorders and cellular abnormalities, and liver metastasis is a common health concern in patients with CRC. Exploring newer and more efficient therapies to block liver metastasis is pivotal for prolonging patient survival. Therefore, small interfering RNAs (siRNAs) are expected to be remarkable tools capable of regulating gene expression by participating in a process called RNA interference (RNAi). RNAi is a biological process among eukaryotes wherein specific messenger RNA (mRNA) molecules are destroyed and gene expression is inhibited. This technology is a promising therapeutic agent in the treatment of CRC liver metastasis (CRLM). Nevertheless, crucial problems in siRNA therapeutics, including inherent poor serum stability and nonspecific uptake into biological systems, must be recognized. For this reason, delivery systems are being developed in an attempt to solve these problems. Here, we discuss the utility of siRNA therapy for the treatment of CRCLM by targeting the major metastasis-related signaling pathways. siRNA therapy has the potential to be one of the most effective methods for CRLM treatment in the future.

Relationship between Fusobacterium nucleatum and antitumor immunity in colorectal cancer liver metastasis.

Fusobacterium nucleatum has been detected in 8%‐13% of human colorectal cancer, and shown to inhibit immune responses against primary colorectal tumors in animal models. Thus, we hypothesized that the presence of F. nucleatum might be associated with reduced T cell density in colorectal cancer liver metastases (CRLM). We quantified F. nucleatum DNA in 181 CRLM specimens using quantitative PCR assay. The densities of CD8+ T cells, CD33+ cells (marker for myeloid‐derived suppressor cells [MDSCs]), and CD163+ cells (marker for tumor‐associated macrophages [TAMs]) in CRLM tissue were determined by immunohistochemical staining. Fusobacterium nucleatum was detected in eight (4.4%) of 181 CRLM specimens. Compared with F. nucleatum‐negative CRLM, F. nucleatum‐positive CRLM showed significantly lower density of CD8+ T cells (P = .033) and higher density of MDSCs (P = .001). The association of F. nucleatum with the density of TAMs was not statistically significant (P = .70). The presence of F. nucleatum is associated with a lower density of CD8+ T cells and a higher density of MDSCs in CRLM tissue. Upon validation, our findings could provide insights to develop strategies that involve targeting microbiota and immune cells for the prevention and treatment of CRLM.

Transarterial chemoembolization of unresectable systemic chemotherapy refractory liver metastases: a retrospective single-center analysis.

The purpose of this study was to evaluate the therapeutic efficacy and safety of transarterial chemoembolization (TACE) in the treatment of patients with unresectable colorectal cancer liver metastases (CRCLM) who had failed systemic chemotherapy. In addition, the role of TACE in the treatment of CRCLM is also worth discussing. This single-center retrospective study evaluated the consecutive medical records of patients with CRCLM treated with TACE from June 2014 to June 2018, who had failed at least two lines of prior chemotherapy. Therapeutic response, overall survival (OS), progression-free survival (PFS), and complications were recorded. Fifty-three eligible patients were included in our study. The objective tumor radiologic regression and disease control rates were 52.8% and 79.2%, respectively. Median OS and PFS were 15 months (95% confidence interval [CI] 13.1 months, 16.9 months) and 6 months (95% CI 4.7 months, 7.3 months), respectively. Multivariate analysis found that synchronous metastatic disease, presence of extrahepatic metastasis, and Child-Pugh score B were independent prognostic factor for OS and PFS. Two patients (3.8%) had severe complications. The results of subgroup analysis showed that synchronous liver metastasis and extrahepatic metastasis had an effect on the prognosis of patients, while the primary tumor sites (rectum, left, and right colon) had no effect on the prognosis. TACE is well tolerated and effective in patients with unresectable chemotherapy refractory CRCLM. Meanwhile, the results of this study also indicated that TACE is still a better treatment for these patients.

Impact of primary tumour location on colorectal liver metastases: A systematic review

BACKGROUNDColorectal cancer (CRC) is the third most common cause of cancer-related death worldwide. Despite significant advances in screening, surgical management and adjuvant therapies, average 5-year survival seldom exceeds 60% in most developed nations. Metastatic disease represents the primary cause of mortality in patients with CRC, and the liver is the most common location for distant tumour spread. Up to 25% of patients are found to have synchronous liver metastases at the time of diagnosis and a further 30%-40% will develop metachronous disease in the course of follow-up. It has been suggested that primary tumour location [right side versus left side, primary tumour location (PTL)] can influence oncological outcomes in this patient group and that this should be considered in prognostic models and therapeutic decision-making algorithms. This suggestion is not universally accepted and there have been conflicting reports in the literature to date.AIMTo provide a comprehensive summary of the available evidence regarding the impact of PTL on oncological outcomes in patients with colorectal cancer liver metastases (CRCLM).METHODSMEDLINE, EMBASE and COCHRANE were searched for relevant publications using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology. Data on oncological outcomes was then extracted from full text articles that met the predefined inclusion criteria.RESULTSA total of 41 studies were identified that met predefined inclusion criteria for this review. In 21 out of 38 studies that provided data on overall survival, a statistically significant improvement in overall survival was reported in patients with left sided primary tumours. These studies included a total of 13897 patients compared with 4306 patients in the studies that did not show a significant difference. Eight studies noted a similar trend towards improved disease-free or progression-free survival. Several authors observed distinct patterns of relapse after treatment of hepatic metastases according to PTL; for example hepatic recurrence after treatment of CRCLM appears to occur more aggressively with right-sided CRC.CONCLUSIONTaken together, the findings of the present review indicate that PTL may have a role as an independent prognostic factor when determining treatment and disease surveillance strategies in CRC. The mechanisms responsible for this variation remain poorly understood, but are likely to relate to molecular, histological and embryological differences, as well as inherent differences in therapeutic sensitivity.

Relaxin-FOLFOX-IL-12 triple combination therapy engages memory response and achieves long-term survival in colorectal cancer liver metastasis

Induction of memory T cell response is inefficient in colorectal cancer (CRC) liver metastasis following existing therapies due to abundant stroma and immunosuppressive environment within the metastatic liver, which leads to fast disease progression, high recurrence rate, and short survival. Two fundamental steps are involved to elicit extensive memory T cell response: stimulation of naive T cells with robust and persistent antigen signals; and maintenance of differentiated memory T cells with survival factors. Here, we demonstrate a rational design of triple combination regimen, including relaxin (RLN), FOLFOX (combination of 5-fluorouracil, leucovorin, and oxaliplatin), and IL-12, successfully stimulates central memory T cells and achieves long-term survival in an aggressive experimental CRC liver metastasis model. Sequential administration of FOLFOX and IL-12 gene therapy following stromal deactivation by RLN gene therapy completely cured established CRC liver metastases in ~50% of mice and provided long-lasting protection against tumor recurrence. The study here may highlight the potential of evoking memory response as a curative therapy for the treatment of CRC liver metastasis.

The Role Of Hepatic Stellate Cells In Promoting Liver Metastasis Of Colorectal Carcinoma.

PurposeColorectal cancer (CRC) is the most common malignancy in the gastrointestinal tract. The liver is the most common location of CRC metastases, which are the main causes of CRC-related death. However, the mechanisms underlying metastasis of CRC to the liver have not been characterized, resulting in therapeutic challenges.MethodsThe effects of hepatic stellate cells (HSCs) on T cells were evaluated using in vitro mixed lymphocyte reactions (MLRs) and cytokine production assays. HSC-induced CT26 cell migration and proliferation were evaluated in vitro and in vivo.ResultsHSCs induced T cell hypo-responsiveness, promoted T cell apoptosis, and induced regulatory T cell expansion in vitro. IL-2 and IL-4 were significantly lower in MLRs incubated with HSCs. Supernatants of MLRs with HSCs promoted CT26 cell proliferation and migration. Furthermore, the presence of HSCs increased the number of liver metastases and promoted proliferation of liver metastatic tumor cells in vivo.ConclusionHSCs may contribute to an immunosuppressive liver microenvironment, resulting in a favorable environment for the colonization of CRC cells in the liver. These findings highlight a potential strategy for treatment of CRC liver metastases.

Perioperative chemotherapy in patients with colorectal cancer liver metastasis

The incidence of colorectal cancer liver metastasis (CRLM) increased gradually in recent years. Surgical resection is the most important treatment for CRLM patients to obtain long-term survival, with a 5-year survival rate of about 50%. However, only 20% of the CRLM patients are initially resectable. The recurrence rate after surgery is more than 70%. Perioperative chemotherapy has been widely used with the development of effective chemotherapy regimens and targeted therapies. For patients with initially resectable liver metastases, perioperative chemotherapy may help reduce recurrence and prolong survival. For patients with unresectable liver metastases, conversion chemotherapy with high efficiency provides opportunity for radical resection. However, CRLM is a disease with high heterogeneity and with many factors influencing prognosis, and there is a lack of large-scale prospective clinical trial evidence in many problems. Hence there are still many controversies in the clinical practice of perioperative chemotherapy, including whether chemotherapy alone is the best preoperative treatment for resectable CRLM, whether preoperative chemotherapy combined with targeted therapy is superior to chemotherapy alone, who can benefit most from preoperative chemotherapy combined with targeted therapy, who are the exact patients suitable for conversion therapy, how to choose the best first-line conversion therapy. Here we discuss the current status of research on perioperative chemotherapy in three aspects: neoadjuvant chemotherapy, conversion therapy and adjuvant chemotherapy. We also emphasized the importance of multidisciplinary team during the treatment process to give patients individualized therapy considering their specific conditions.