Molecular targets and mechanisms of different aberrant alternative splicing in metastatic liver cancer

Metastasis remains a major challenge in the successful management of malignant diseases.The liver is a major site of metastatic disease and a leading cause of death from gastrointestinal malignancies such as colon,stomach,and pancreatic cancers,as well as melanoma,breast cancer,and sarcoma.As an important factor that influences the development of metastatic liver cancer,alternative splicing drives the diversity of RNA transcripts and protein subtypes,which may provide potential to broaden the target space.In particular,the dysfunction of splicing factors and abnormal expression of splicing variants are associated with the occurrence,progression,aggressiveness,and drug resistance of cancers caused by the selective splicing of specific genes.This review is the first to provide a detailed summary of the normal splicing process and alterations that occur during metastatic liver cancer.It will cover the role of alternative splicing in the mechanisms of metastatic liver cancer by examining splicing factor changes,abnormal splicing,and the contribution of hypoxia to these changes during metastasis.

Study of angiogenesis induced by metastatic and non-metastatic liver cancer by corneal micropocket model in nude mice

AIM To study the angiogenesis induced by liver cancer with different metastatic potentials using corneal micropocket model in nude mice.METHODS Corneal micropockets were created in nude mice. Tumor tissues and liver tissues were implanted into the corneal micropockets. Angiogenesis was observed using a digital camera under slit-lamp biomicroscope, and compared among different grafts and incision alone. Vascular responses were recorded in regard to the range, number and length of new blood vessels toward the grafts or incisions.RESULTS Vascular responses induced by tumor tissues were greater than those by incision alone and liver tissue grafts. LCI-D20 induced more intensive angiogenesis than LCI-D35.CONCLUSION Highly metastatic liver cancer LCI D20 was more angiogenic than low metastatic cancer LCI D35 and liver tissue. Micropocket was a useful model to study dynamic process of angiogenesis in vivo.

Evolution in the treatment of metastatic colorectal carcinoma of the liver

Metastatic colorectal cancer to the liver is associated with a uniform poor prognosis without treatment. Advances in therapy over the past decades have now allowed surgical resections of the liver to occur with a low morbidity and mortality. Improvements in chemotherapy regimes have paralleled technical improvements and now allow a new group of patients to become eligible for surgical resection. This chapter will review the recent advances in surgical and chemotherapeutic regimes in metastatic colorectal cancer to the liver.

Silencing phospholipid scramblase 1 expression by RNA interference in colorectal cancer and metastatic liver cancer

BACKGROUND:Phospholipid scramblase 1(PLSCR1) not only participates in the transbilayer movement of phospholipids,but also plays a role in the pathogenesis and progression of cancers.The present study aimed to evaluate the effect of silencing PLSCR1 expression by RNA interference in colorectal cancer(CRC) and metastatic liver cancer.METHODS:The expression of PLSCR1 in CRC and metastatic liver cancer samples was assessed by immunohistochemistry.The cultured cells with the highest expression were selected for subsequent experiments.We designed three siRNA oligonucleotide segments targeted at PLSCR1.Successful transfection was confirmed.The biological behavior of the cells in proliferation,adhesion,migration and invasion was determined.RESULTS:PLSCR1 protein expression increased significantly in the majority of CRC and metastatic liver cancer samples compared with normal samples.Lovo cells had the highest expression of PLSCR1.The siRNA-390 oligonucleotide segment had the best silencing effect.After transfection,Lovo cell proliferation was significantly inhibited compared with the controls in the MTT assay.Laminin and fibronectin adhesion assays showed Lovo cell adhesion was also significantly inhibited.In the migration assay,the number of migrating cells in the PLSCR1 siRNA-390 group was 50±12,significantly lower than the number in the siRNA-N group(115±28) and in the control group(118±31).In an invasion test,the number of invading cells in the PLSCR1 siRNA-390 group was 60±18,significantly lower than that in the siRNA-N group(97±26) and the control group(103±24).CONCLUSIONS:PLSCR1 is overexpressed in CRC and metastatic liver cancer.Silencing of PLSCR1 by siRNA inhibits the proliferation,adhesion,migration and invasion of Lovo cells,which suggests that PLSCR1 contributes to the tumorigenesis and tumor progression of CRC.PLSCR1 may be a potential gene therapy target for CRC and associated metastatic liver cancer.

Macrophage inflammatory protein-2 contributes to liver resection-induced acceleration of hepatic metastatic tumor growth

AIM： To study the role of macrophage inflammatory protein （HIP）-2 in liver resection-induced acceleration of tumor growth in a mouse model of hepatic metastasis. METHODS： After a 50% hepatectomy, 1×10^5 CT26.WT cells were implanted into the left liver lobe of syngeneic balb/c mice （PHx）. Additional animals were treated with a monoclonal antibody （HAB452） neutralizing HIP-2 （PHx＋mAB）. Non-resected and non-mAB-treated mice （Con） served as controls. After 7 d, tumor angiogenesis and microcirculation as well as cell proliferation, tumor growth, and CXCR-2 expression were analyzed using in- travital fluorescence microscopy, histology, immunohisto- chemistry, and flow cytometry. RESULTS： Partial hepatectomy increased （P〈0.05）the expression of the HIP-2 receptor CXCR-2 on tumor cells when compared with non-resected controls, and markedly accelerated （P〈 0.05） angiogenesis and metastatic tumor growth. Neutralization of HIP-2 by HAB452 treatment significantly （P〈 0.05） depressed CXCR-2 expression. Further, the blockade of MIP-2 reduced the angiogenic response （P〈 0.05） and inhibited tumor growth （P〈 0.05）. Of interest, liver resection-induced hepatocyte proliferation was not effected by anti-HIP-2 treatment. CONCLUSION： HIP-2 significantly contributes to liver resection-induced acceleration of colorectal CT26.WT hepatic metastasis growth.

Prognostic role of platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio in patients with non-metastatic and metastatic prostate cancer:A meta-analysis and systematic review

Objective: To analyze data available in the literature regarding a possible prognostic value of the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) in prostate cancer (PCa) patients stratified in non-metastatic and metastatic diseases.Methods: A literature search process was performed following the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. In our meta-analysis, the pooled event rate estimated and the pooled hazard ratio were calculated using a random effect model.Results: Forty-two articles were selected for our analysis. The pooled risk difference for non-organ confined PCa between high and low NLR cases was 0.06 (95% confidence interval [CI]: −0.03-0.15) and between high and low PLR cases increased to 0.30 (95% CI: 0.16-0.43). In non-metastatic PCa cases, the pooled hazard ratio for overall mortality between high and low NLR was 1.33 (95% CI: 0.78-1.88) and between high and low PLR was 1.47 (95% CI: 0.91-2.03), whereas in metastatic PCa cases, between high and low NLR was 1.79 (95% CI: 1.44-2.13) and between high and low PLR was 1.05 (95% CI: 0.87-1.24).Conclusion: The prognostic values of NLR and PLR in terms of PCa characteristics and responses after treatment show a high level of heterogeneity of results among studies. These two ratios can represent the inflammatory and immunity status of the patient related to several conditions. A higher predictive value is related to a high NLR in terms of risk for overall mortality in metastatic PCa cases under systemic treatments.

Evaluation of Lipid Peroxidation and Some Antioxidant Activities in Patients with Primary and Metastatic Liver Cancer

Abstract: HCC is the 6th most common cancer in the world. The main risk factors associated with HCC are hepatitis B (HBV) and hepatitis C viral infections and other factors that play a role in HCC development, include aflatoxin B1 (AFB1) cigarette smoking, and chronic inflammation. The aim of this study is to investigate lipid peroxidation and some antioxidant enzyme activities in patients with primary and metastatic liver cancer. For this purpose, 25 primary and metastatic liver cancer patients and 15 healthy controls were included in the study. In blood samples taken from the patient and control groups, the main product of lipid peroxidation MDA and SOD, GSH, GPx activity levels were examined. In result of study serum MDA level is higher and erythrocyte SOD, GSH, and GPx activities were found to be significantly lower in the patient group compared with the control group (p 0.05). As a result, liver cancer is associated with oxidative stress and antioxidant system weakens, which is an important indicator of oxidative stress, lipid peroxidation levels increased and promotes the tissue damage.

Focal peliosis hepatis in a colon cancer patient resembling metastatic liver tumor

Peliosis hepatis(PH) is a rare benign condition characterized by the presence of multiple,randomly distributed,blood filled cystic areas of variable size within the liver parenchyma.PH is difficult to recognize and may be mistaken for neoplasm,metastases or multiple abscesses.A 75-year-old female with a previous history of colon cancer was admitted when a liver mass in the right liver lobe was found 11 mo after surgery during the follow-up period.Computed tomography and magnetic resonance imaging scan of the abdomen were performed.The initial possible diagnosis was metastatic hepatocellular carcinoma.The patient underwent excision of the hepatic segment where the nodule was located.The pathological diagnosis of the surgical specimen was PH.PH should be considered in the differential diagnosis of new liver lesions in patients whose clinical settings do not clearly favor metastasization.Clinicians and radiologists must recognize these lesions to minimize the probability of misdiagnosis and inappropriate treatment.

Acute autoimmune hepatitis mimicking metastatic liver disease: A case report

We report progressive painless jaundice in a 39 year old female with a suspicion of metastatic liver disease on ultrasound and computed tomography scan of the abdomen. Although the most frequent liver lesions are liver metastasis because of dual blood supply of the liver and the impact of hormones, the index case proved to have acute autoimmune hepatitis (AIH) after liver biopsy was undertaken. AIH, an unresolving inflammation of liver, occurs predominantly among females worldwide. It may present acutely and even fulminant hepatitis has been described. The index case had a dramatic response to steroid treatment with total recovery and complete resolution of liver lesions. She is clinically fine and has been regularly attending our clinic for the last year. To our knowledge from a Medline search, this is the first report where AIH was seen to mimic metastatic liver disease.

Limited influences of chemotherapy on healthy and metastatic liver parenchyma

AIM: To examine the expression of E-cadherin, β-catenin,γ-catenin, VEGF, and p53 in 39 patients with hepatic metastasis from colorectal cancer immunohistochemically.METHODS: The patients were divided into two groups:those (n = 16) who had no chemotherapy for at least 6 mo before the liver resections and those (n = 23)who were treated with chemotherapy before liver resections. A score from 0 to 3 was given for the number of positive cells and from 0 to 3 for the intensity of staining in these cells, in both healthy and metastatic liver parenchyma.RESULTS: No significant differences in the expression of E-cadherin, β- and γ-catenin, VEGF and p53, could be observed between patients who received and did not receive chemotherapy, in both normal and metastatic liver parenchyma.CONCLUSION: Despite the assumption that chemotherapy had an effect on liver metastasis, no influences were noticed immunohistochemically.

Current status of yttrium-90 microspheres radioembolization in primary and metastatic liver cancer

Liver malignancy,including primary liver cancer and metastatic liver cancer has become one of the most common causes of cancer-related death worldwide due to the high malignant degree and limited systematic treatment strategy.Radioembolization with yttrium-90(^(90)Y)-loaded microspheres is a relatively novel technology that has made significant progress in the local treatment of liver malignancy.The different steps in the extensive work-up of radioembolization for patients with an indication for treatment with^(90)Y microspheres,from patient selection to follow up,both technically and clinically,are discussed in this paper.It describes the application and development of^(90)Y microspheres in the treatment of liver cancer.

Metastatic disease to the liver:Locoregional therapy strategies and outcomes

Secondary cancers of the liver are more than twenty times more common than primary tumors and are incurable in most cases.While surgical resection and systemic chemotherapy are often the first-line therapy for metastatic liver disease,a majority of patients present with bilobar disease not amenable to curative local resection.Furthermore,by the time metastasis to the liver has developed,many tumors demonstrate a degree of resistance to systemic chemotherapy.Fortunately,catheter-directed and percutaneous locoregional approaches have evolved as major treatment modalities for unresectable metastatic disease.These novel techniques can be used for diverse applications ranging from curative intent for small localized tumors,downstaging of large tumors for resection,or locoregional control and palliation of advanced disease.Their use has been associated with increased tumor response,increased disease-free and overall survival,and decreased morbidity and mortality in a broad range of metastatic disease.This review explores recent advances in liver-directed therapies for metastatic liver disease from primary colorectal,neuroendocrine,breast,and lung cancer,as well as uveal melanoma,cholangiocarcinoma,and sarcoma.Therapies discussed include bland transarterial embolization,chemoembolization,radioembolization,and ablative therapies,with a focus on current treatment approaches,outcomes of locoregional therapy,and future directions in each type of metastatic disease.

Neoadjuvant chemotherapy for metastatic colorectal cancer to the liver: from chemotherapy to targeting therapy

Despite the advances in surgical techniques, adjuvant chemotherapy and targeted therapy, approximately 40%-70% of patients with progressive colorectal cancer will develop liver metastases, of whom one-third are found at the time of diagnosis.[1] Surgical resection is now the standard treatment and also the only potentially curative treatment for resectable lesions.

Prognostic impact of metastatic lymph node ratio on gastric cancer after curative distal gastrectomy

AIM:To investigate the prognostic impact of metastatic lymph node ratio(rN) on gastric cancer after curative distal gastrectomy.METHODS:A total of 634 gastric cancer patients who underwent curative resection(R0) of lymph nodes at distal gastrectomy in 1995-2004.Correlations between positive nodes and retrieved nodes,between rN and retrieved nodes,and between rN and negative lymph node(LN) count were analyzed respectively.Prognostic factors were identif ied by univariate and multivariate analyses.Staging accuracy of the pN category(5th UICC/TNM system) and the rN category was compared according to the survival rates of patients.A linear regression model was used to identify the relation between rN and 5-year survival rate of the patients.RESULTS:The number of dissected LNs was related with metastatic LNs but not related with rN.Cox regression analysis showed that depth of invasion,pN and rN category were the independent predictors of survival(P < 0.05).There was a signif icant difference in survival between LN stages classif ied by the rN category or by the pN category(P < 0.05).However,no signif icant difference was found in survival rate between LN stages classif ied by the pN category or by the rN category(P > 0.05).Linear regression model showed a signif icant linear correlation between rN and the 5-year survival rate of gastric cancer patients(β = 0.862,P < 0.001).Pearson's correlation test revealed that negative LN count was negatively correlated with rN(P < 0.001).CONCLUSION:rN category is a better prognostic tool than the 5th UICC pN category for gastric cancer patients after curative distal gastrectomy.Increased negative LN count can reduce rN and improve the survival rate of gastric cancer patients.

Serum vascular endothelial growth factor is a potential biomarker of metastatic recurrence after curative resection of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignancies in China. To date, surgery is still the best solution to it. However, metastatic recurrences after curative hepatic resections are very common. Tang et al have reported that recurrence rate within 5 years of curative hepatic resection is 61.5% [1]. As curative hepatic resection has a high tendency for metastatic recurrence, therapeutic interventions such as transarterial embolization and antiangiogenesis have been tried to further improve prognosis of HCC patients. Therefore, establishing a dependable, sensitive, easy, and economical method to predict metastatic recurrence following curative hepatic resection is of clinical urgency.

Alterations in metastatic properties of hepatocellular carcinoma cell following H-ras oncogene transfection

AIM: To demonstrate the relationship between H-ras oncogene and hepatocellular carcinoma (HCC) metastasis. METHODS: Activated H-ras oncogene was transfected into SMMC 7721, a cell line derived from human HCC, by calcium phosphate transfection method. Some metastasis-related parameters were detected in vitro, including adhesion assay, migration assay, expression of collagenase IV(c IV ase) and epidermal growth factor receptor (EGFR). RESULTS: The abilities of H-ras-transfected cell clones in adhesion to laminin (LN) or fibronectin (FN), migration, c IV ase secretion increased markedly, and the expression of EGFR elevated moderately. More importantly, these alterations were consistent positively with the expression of p21, the protein product of H-ras oncogene. CONCLUSION: H-ras oncogene could induce the metastatic phenotype of HCC cell in vitro to raise its metastatic potential.

Neoplastic disease after liver transplantation: focus on de novo neoplasms

De novo neoplasms account for almost 30% of deaths 10 years after liver transplantation and are the most common cause of mortality in patients surviving at least 1 year after transplant. The risk of malignancy is two to four times higher in transplant recipients than in an age- and sex-matched population, and cancer is expected to surpass cardiovascular complications as the primary cause of death in transplanted patients within the next 2 decades. Since exposure to immunosuppression is associated with an increased frequency of developing neoplasm, long-term immunosuppression should be therefore minimized. Promising results in the prevention of hepatocellular carcinoma(HCC) recurrence have been reported with the use of m TOR inhibitors including everolimus and sirolimus and the ongoing open-label prospective randomized controlled SILVER. Study will provide more information on whether sirolimus-containing vs m TOR-inhibitorfree immunosuppression is more efficacious in reducing HCC recurrence.

Moving toward an understanding of the metastatic process in hepatocellular carcinoma

INTRODUCTIONClinical factors contributing to the therapeutic challenge of hepatocellular carcinoma (HCC) are manifold :tumors arise often in patients with compromised liver function ,therefore limiting therapeutic options ;symptoms develop only at later stages of tumor progression ,and tumors tend to invade normal stuctures or occur in multiple locations simultaneously.

Neuroendocrine neoplasms of liver-A 5-year retrospective clinico-pathological study applying World Health Organization 2010 classification

AIM To study the clinicopathological characteristics of neuroendocrine neoplasms(NEN) on liver samples and apply World Health Organization(WHO) 2010 grading of gastroenteropancreatic(GEP) NEN.METHODS Clinicopathological features of 79 cases of NEN of the liver diagnosed between January 2011 to December 2015 were analyzed. WHO 2010 classification of GEP NEN was applied and the tumors were graded as G1, G2 or G3. Two more categories, D1/2(discordant 1/2) and D2/3(discordant 2/3) were also applied. The D1/2 grade tumors had a mitotic count of G1 and Ki-67 index of G2. The D2/3 tumors had a mitotic count of G2 and Ki-67 index of G3. The follow up details which were available till the end of the study period(December 2015) were collected.RESULTS Of the 79 tumors, 16 each were G1 and G2, and 18 were G3 tumors. Of the remaining 29 tumors, 13 were assigned to D1/2 and 16 were D2/3 grade. Male preponderance was noted in all tumors except for G2 neoplasms, which showed a slight female predilection. The median age at presentation was 47 years(range 10-82 years). The most common presentation was abdominal pain(81%). Pancreas(49%) was the most common site of primary followed by gastrointestinal tract(24.4%) and lungs(18%). Radiologically, 87% of the patients had multiple liver lesions. Histopathologically, necrosis was seen in only D2/3 and G3 tumors. Microvascular invasion was seen in all grades. Metastasis occurred in all grades of primary NEN and the grades of the metastatic tumors and their corresponding primary tumors were similar in 67% of the cases. Of the 79 patients, 36 had at least one follow up visit with a median duration of follow up of 8.5 mo(range: 1-50 mo). This study did not show any impact of the grade of tumor on the short term clinical outcome of these patients.CONCLUSION Liver biopsy is an important tool for clinicopathological characterization and grading of NEN, especially when the primary is not identified. Eighty-seven percent of the patients had multifocal liver lesions irrespective of the WHO grade, indicating a higher stage of disease at presentation. Follow up duration was inadequate to derive any meaningful conclusion on long term outcome in our study patients.

Transarterial chemoembolization for liver metastases from solid pseudopapillary epithelial neoplasm of pancreas: A case report

Solid pseudo-papillary epithelial neoplasm(SPEN) is a rare epithelial tumor of pancreas with a low malignant potential occurs most commonly in young females. We report a case of 40 years old woman presented withextensive liver metastasis from SPEN of pancreatic body for which she was operated four years ago. Due to the extensive nature of metastatic disease she was offered Transarterial chemoembolisation(TACE) using gemcitabine as chemotherapeutic agent. Short term follow up after a month of TACE with multiphase computed tomography showed > 90% resolution in the viable tumor with significant clinical improvement. TACE ensures targeted delivery of chemotherapeutic drugs in higher doses with least systemic toxicity and is more effective and safe than systemic chemotherapy. TACE with gemcitabine was found to be very effective in our patient with numerous liver metastasis.