Hepatocellular carcinoma(HCC) is the most frequent primary liver malignancy and the third cause of cancer-related death in the Western Countries. The well-established causes of HCC are chronic liver infections such as...Hepatocellular carcinoma(HCC) is the most frequent primary liver malignancy and the third cause of cancer-related death in the Western Countries. The well-established causes of HCC are chronic liver infections such as hepatitis B virus or chronic hepatitis C virus, nonalcoholic fatty liver disease, consumption of aflatoxins and tobacco smocking. Clinical presentation varies widely; patients can be asymptomatic while symptomatology extends from right upper abdominal quadrant paint and weight loss to obstructive jaundice and lethargy. Imaging is the first key and one of the most important aspects at all stages of diagnosis, therapy and follow-up of patients with HCC. The Barcelona Clinic Liver Cancer Staging System remains the most widely classification system used for HCC management guidelines. Up until now, HCC remains a challenge to early diagnose, and treat effectively; treating management is focused on hepatic resection, orthotopic liver transplantation, ablative therapies, chemoembolization and systemic therapies with cytotocix drugs, and targeted agents. This review article describes the current evidence on epidemiology, symptomatology, diagnosis and treatment of hepatocellular carcinoma.展开更多
AIM： The role of the appendix has been highlighted in the pathogenesis of ulcerative colitis （UC）. The aims of this study were to elucidate the immuno-imbalances in the appendix of UC patients, and to clarify the r...AIM： The role of the appendix has been highlighted in the pathogenesis of ulcerative colitis （UC）. The aims of this study were to elucidate the immuno-imbalances in the appendix of UC patients, and to clarify the role of the appendix in the development of UC. METHODS： Colonoscopic biopsy specimens of the appendix, transverse colon, and rectum were obtained from 86 patients with UC： active pancolitis （A-Pan; n = 15）, active letf-sided colitis （A-Lt; n = 25）, A-Lt with appendiceal involvement （A-Lt/Ap; n = 10）, inactive pancolitis （I-Pan; n = 14）, and inactive left-sided colitis （I-Lt; n = 22）, and from controls. In the isolated mucosal T cells, the CD4/CD8 ratio and proportion of activated CD4＋ T ceils were investigated, and compared with controls. RESULTS： in the appendix, the CD4/CD8 ratio significantly increased in A-Lt and A-Lt/Ap. The ratio in the appendix also tended to increase in A-Pan. In the rectum, the ratio significantly increased in all UC groups. In the appendix, the proportion of CD4＋CD69＋ （early activation antigen） T cells significantly increased in all UC groups. In the rectum, the proportion of CD4＋CD69＋ T cells significantly increased only in A-Pan. The proportion of CD4＋HLADR＋ （mature activation antigen） T cells significantly increased only in the rectum of A-Pan, but not in the otherareas of any groups. CONCLUSION： The increased CD4/CD8 ratio and predominant infiltration of CD4＋CD69＋ T cells in the appendix suggest that the appendix is a priming site in the development of UC.展开更多
INTRODUCTION Since 1982,Helicobacter pylori(Hp) has been successfully isolated and cultured,and the fact many diseases such as gastritis,peptic ulcer,gastric carcinoma
Tumors of the pancreas,the ampulla of Vater,and the extrahepatic and intrahepatic bile ducts have significant histological similarities due to the common embryonic origin of the pancreatobiliary system.This obviates t...Tumors of the pancreas,the ampulla of Vater,and the extrahepatic and intrahepatic bile ducts have significant histological similarities due to the common embryonic origin of the pancreatobiliary system.This obviates the need for discovery of biomarkers with diagnostic and prognostic value for these tumors.Mucins,especially MUC-1,-2,-4 and-5AC,are important candidates for developing into such reliable biomarkers.Increased expression of MUC1 occurs in pancreatic ductal adenocarcinomas and is associated with increased degrees of dysplasia in pancreatic intraepithelial neoplasia(Pan IN).Positive expression of MUC2 in intraductal papillary mucinus neoplasms(IPMN) of the intestinal type indicates high potential progression to invasive carcinoma with de novo expression of MUC1,while absence of MUC2 expression in IPMNs of gastric type implies low potential to malignant evolution.De novo MUC4 expression correlates to the severity of dysplasia in Pan IN and is associated with a poor prognosis in patients with pancreatic ductal adenocarcinomas.In biliary intraepithelial neoplasia(Bil IN),increased expression of MUC1 is associated with higher degrees of dysplasia.Intrahepatic cholangiocarcinomas(ICC) are characterized by increased expression of all glycoforms of MUC1.Positive MUC2 expression in intraductal papillary neoplasm of the bile ducts(IPNB) of the intestinal type indicates high malignant potential with de novo expression of MUC1 in the invasive element.Absent MUC2 expression in any degree of Bil IN may prove useful in differentiating them from IPNB.De novo expression of MUC4 is associated with poor prognosis in patients with ICC or carcinoma of the extrahepatic bile ducts(EHBDC).High de novo expression of MUC5 AC is found in all degrees of Bil IN and all types of IPNB and ICC.The MUC5 AC is useful in the detection of neoplastic lesions of the bile duct at an early stage.Increased expression of mucin MUC1 in carcinoma of the ampulla of Vater associated with unfavorable behavior of the tumor,such as lymph node metastasis,infiltration of the pancreas and duodenum,advanced TNM classification and worse prognosis.Patients withintra-ampullary papillary-tubular neoplasm(IAPN) of the pancreatobiliary immunophenotype did not show MUC2,while those of the intestinal immunophenotype are MUC2 positive.The expression of MUC4 is associated with poor prognosis in patients with carcinoma of the ampulla of Vater favoring metastasis and making them resistant to apoptosis.Moreover,it appears that MUC4 positivity correlates with recurrence of the tumor.Expression of MUC5 AC is associated with the invasive potential of the tumor.展开更多
INTRODUCTION Secondary amyloidosis is a rare but seriouscomplication of Crohn’s disease(CD).Theincidence of the association of secondaryamyloidosis in patients with CD has been reportedto be 0.5%-8% in Western countr...INTRODUCTION Secondary amyloidosis is a rare but seriouscomplication of Crohn’s disease(CD).Theincidence of the association of secondaryamyloidosis in patients with CD has been reportedto be 0.5%-8% in Western countries.However,in Japan,the number of patients with CDcomplicated by amyloidosis is limited.Thecharacteristics of their clinical manifestations andthe incidence of association are uncertain.Therefore,we report herein a patient with展开更多
BACKGROUND:Although invasive ductal adenocarcinoma of the pancreas(PDAC) manifests as a relatively uniform histomorphological feature of the pancreatobiliary type,it may be complicated by metaplastic changes and heter...BACKGROUND:Although invasive ductal adenocarcinoma of the pancreas(PDAC) manifests as a relatively uniform histomorphological feature of the pancreatobiliary type,it may be complicated by metaplastic changes and heterogeneous gastric and intestinal elements.This study aimed to investigate the complication rate and clinicopathological significance of such heterogeneous elements.METHODS:Fifty-nine patients who underwent resection of PDAC were examined in this study.Immunohistochemically,tumors showing high expression(>25%) of the intestinal-type(INT) marker CDX2 were classified as PDAC with INT.Those with high expression(>25%) of the gastric-type(GAS) marker MUC5AC were classified as PDAC with GAS,while those with high expression of both markers were classified as PDAC with INT/GAS.These patients were compared with those with PDAC of the negative group in which neither markers was highly expressed to examine their clinicopathological significance.RESULTS:In the 59 patients,31(52.5%) showed high CDX2 or MUC5AC expression.Twenty-eight patients(47.5%) belonged to a negative group,11(18.6%) to a PDAC with INT group,15(25.4%) to a PDAC with GAS group,and 5(8.5%) to a PDAC with INT/GAS group.No significant differences were observed for age,gender,size,localization,T classification,or prognosis among the four groups.Although the PDAC with GAS group had well differentiated types significantly more than the other groups,the rate of lymph node metastasis in this group was significantly higher(PDAC with GAS:73%;other groups:36%).CONCLUSION:Complications with heterogeneous elements are not uncommon in PDAC,and this should be considered during the diagnosis and treatment of PDAC along with histogenesis of the disease.展开更多
The ventral quadrant of the tracheal epithelium of the hamster,about one fourth of tracheal mucosa, was denuded by a venous needle reformed.The stains were made with HE, PAS, and PAS-anti Brdu immunohis-tochemic techn...The ventral quadrant of the tracheal epithelium of the hamster,about one fourth of tracheal mucosa, was denuded by a venous needle reformed.The stains were made with HE, PAS, and PAS-anti Brdu immunohis-tochemic technique. At the 0 h circumference cell number (CCN) was 927. 25.From 6 h post injured the viable cells changed in shapes and migrated from themargin to wound site. By 24 h the wound area was completely covered by a sin-gle layer of non-ciliated flattened cells, then an expotential increassing in cellregeneration occured in wound site by 48 h. The CCN had been restored to thelevel of control (1373), and the proliferative cell, composed of polygonal epi-dermoid metaplasia, 3～4 layers and reached a peak (338.8). The secretoryand ciliated cells appeared gradually from 72 h post injury, the epithelium re-stored to the normal epithelial architecture by one week post injury. In our pre-sent study either in control and non-injured epithelium or in all stages of woundsite about 70% of the Brdu positive cells contained small or confluent PAS posi-tive granules were observed. This fact indicated that secretory cells play a im-portant role in proliferation after mechanical injury and maintaining the normaltracheal pseudostratified epithelium.展开更多
Colorectal cancer(CRC) constitutes the third most frequently reported malignancy in the male population and the second most common in women in the last two decades. Colon carcinogenesis is a complex, multifactorial ev...Colorectal cancer(CRC) constitutes the third most frequently reported malignancy in the male population and the second most common in women in the last two decades. Colon carcinogenesis is a complex, multifactorial event, resulting from genetic and epigenetic aberrations, the impact of environmental factors, as well as the disturbance of the gut microbial ecosystem. The relationship between the intestinal microbiome and carcinogenesis was relatively undervalued in the last decade. However, its remarkable effect on metabolic and immune functions on the host has been in the spotlight as of recent years. There is a strong relationship between gut microbiome dysbiosis, bowel pathogenicity and responsiveness to anti-cancer treatment;including immunotherapy. Modifications of bacteriome consistency are closely associated with the immunologic response to immunotherapeutic agents. This condition that implies the necessity of gut microbiome manipulation. Thus, creatingan optimal response for CRC patients to immunotherapeutic agents. In this paper, we will review the current literature observing how gut microbiota influence the response of immunotherapy on CRC patients.展开更多
Proteoglycans are a group of molecules that contain at least one glycosaminoglycan chain,such as a heparan,dermatan,chondroitin,or keratan sulfate,covalently attached to the protein core.These molecules arecategorized...Proteoglycans are a group of molecules that contain at least one glycosaminoglycan chain,such as a heparan,dermatan,chondroitin,or keratan sulfate,covalently attached to the protein core.These molecules arecategorized based on their structure,localization,and function,and can be found in the extracellular matrix,on the cell surface,and in the cytoplasm.Cell-surface heparan sulfate proteoglycans,such as syndecans,are the primary type present in healthy liver tissue.However,deterioration of the liver results in overproduction of other proteoglycan types.The purpose of this article is to provide a current summary of the most relevant data implicating proteoglycans in the development and progression of human and experimental liver cancer.A review of our work and other studies in the literature indicate that deterioration of liver function is accompanied by an increase in the amount of chondroitin sulfate proteoglycans.The alteration of proteoglycan composition interferes with the physiologic function of the liver on several levels.This article details and discusses the roles of syndecan-1,glypicans,agrin,perlecan,collagen XVIII/endostatin,endocan,serglycin,decorin,biglycan,asporin,fibromodulin,lumican,and versican in liver function.Specifically,glypicans,agrin,and versican play significant roles in the development of liver cancer.Conversely,the presence of decorin could potentially provide protective effects.展开更多
Pancreatic cancer is one of the most aggressive human cancers,with more than 200 000 deaths worldwide every year.Despite recent efforts,conventional treatment approaches,such as surgery and classic chemotherapy,have o...Pancreatic cancer is one of the most aggressive human cancers,with more than 200 000 deaths worldwide every year.Despite recent efforts,conventional treatment approaches,such as surgery and classic chemotherapy,have only slightly improved patient outcomes.More effective and well-tolerated therapies are required to reverse the current poor prognosis of this type of neoplasm.Among new agents,histone deacetylase inhibitors (HDACIs) are now being tested.HDACIs have multiple biological effects related to acetylation of histones and many non-histone proteins that are involved in regulation of gene expression,apoptosis,cell cycle progression and angiogenesis.HDACIs induce cell cycle arrest and can activate the extrinsic and intrinsic pathways of apoptosis in different cancer cell lines.In the present review,the main mechanisms by which HDACIs act in pancreatic cancer cells in vitro,as well as their antiproliferative effects in animal models are presented.HDACIs constitute a promising treatment for pancreatic cancer with encouraging anti-tumor ef-fects,at well-tolerated doses.展开更多
AIM： To characterize the alpha-fetoprotein （AFP） positive and negative hepatocellular carcinoma （HCC） samples. METHODS： Thirty-seven paraffin-embedded human HCC samples were analyzed by immunohistochemistry for ...AIM： To characterize the alpha-fetoprotein （AFP） positive and negative hepatocellular carcinoma （HCC） samples. METHODS： Thirty-seven paraffin-embedded human HCC samples were analyzed by immunohistochemistry for the following antigens： AFP,β-catenin, p53, CD44, MSH-2, MLH-1, and HNF-4. The tumors were divided into two groups based on the AFP expression. The immunophenotypic data and important clinical parameters were studied between the two groups. RESULTS： Twenty-one of the thirty-seven examined HCCs were AFP positive. Seven with nudear p53 staining were AFP positive, while seven tumors with nuclear β-catenin staining were AFP negative. CD44 staining and high histological tumor grade were more frequent among the AFP-positive HCCs. The other immunophenotypical and dinical parameters did not show statistically significant difference in their distribution between the AFP positive and negative samples. CONCLUSION： AFP expression in HCC correlates with unfavorable prognostic factors, while nuclear β-catenin positivity is more common among the AFP-negative liver tumors. This observation supports the microarray data on in vivo human tumors.展开更多
Despite reduction of hepatitis C prevalence after recognition of the virus and testing of blood products, hemodialysis(HD) patients still comprise a high risk group. The natural history of hepatitis C virus(HCV) infec...Despite reduction of hepatitis C prevalence after recognition of the virus and testing of blood products, hemodialysis(HD) patients still comprise a high risk group. The natural history of hepatitis C virus(HCV) infection in dialysis is not fully understood while the clinical outcome differs from that of the general population. HD patients show a milder liver disease with lower aminotransferase and viral levels depicted bymilder histological features on liver biopsy. Furthermore, the "silent" clinical course is consistent with a slower disease progression and a lower frequency of cirrhosis and hepatocellular carcinoma. Potential explanations for the "beneficial" impact of uremia and hemodialysis on chronic HCV infection are impaired immunosurveillance leading to a less aggressive host response to the virus and intradialytic release of "hepatoprotective" cytokines such as interferon(IFN)-α and hepatocyte growth factor. However, chronic hepatitis C is associated with a higher liver disease related cardiovascular and allcause mortality of HD patients. Therapy is indicated in selected patients groups including younger patients with low comorbidity burden and especially renal transplant candidates, preferably after performance of a liver biopsy. According to current recommendations, choice of treatment is IFN or pegylated interferon with a reported sustained viral response at 30%-40% and a withdrawal rate ranging from 17% to 30%. New data regarding combination therapy with low doses of ribavirin which provide higher standard variable rates and good safety results, offer another therapeutic option. The new protease inhibitors may be the future for HCV infected HD patients, though data are still lacking.展开更多
BACKGROUND The differences in histopathology and molecular biology between right colon cancer(RCC)and left colon cancer(LCC)were first reported in the literature by Bufill in 1990.Since then,a large number of studies ...BACKGROUND The differences in histopathology and molecular biology between right colon cancer(RCC)and left colon cancer(LCC)were first reported in the literature by Bufill in 1990.Since then,a large number of studies have confirmed their differences in epidemiology,clinical presentation,comorbidities and biological behaviours,which may be related to the difference in prognosis and overall survival(OS)between the two groups.AIM To investigate statistically significant differences between Greek patients with LCC and RCC.METHODS The present observational study included 144 patients diagnosed with colon cancer of any stage who received chemotherapy in a Greek tertiary oncology hospital during a 2.5-year period.Clinical information,comorbidities,histopathologic characteristics and molecular biomarkers were collected from the patients’medical records retrospectively,while administered chemotherapy regimens,targeted agents,progression-free survival(PFS)periods with first-and second-line chemotherapy and OS were recorded retroactively and prospectively.Data analysis was performed with the SPSS statistical package.RESULTS Eighty-six males and 58 females participated in the study.One hundred(69.4%)patients had a primary lesion in the left colon,and 44(30.6%)patients had a primary lesion in the right colon.Patients with RCC were more likely to display anaemia than patients with LCC[odds ratio(OR)=3.09],while LCC patients were more likely to develop rectal bleeding(OR=3.37)and a feeling of incomplete evacuation(OR=2.78)than RCC patients.Considering comorbidities,RCC patients were more likely to suffer from diabetes(OR=3.31)and coronary artery disease(P=0.056)than LCC patients.The mucinous differentiation rate was higher in the right-sided group than in the left-sided group(OR=4.49),as was the number of infiltrated lymph nodes(P=0.039),while the percentage of high-grade differentiation was higher in the group of patients with left-sided colon cancer than in RCC patients(OR=2.78).RAS wild-type patients who received anti-epidermal growth factor receptor(EGFR):Treatment experienced greater benefit(PFS:16.5 mo)than those who received anti-vascular endothelial growth factor treatment(PFS:13.7 mo)(P=0.05),while among RAS wild-type patients who received anti-EGFR treatment,LCC patients experienced greater benefit(PFS:15.8 mo)than the RCC subgroup(PFS:5.5 mo)in the first-line chemotherapy setting(P=0.034).BRAF-mutant patients had shorter PFS(9.3 mo)than BRAF wild-type patients(14.5 mo)(P=0.033).RCC patients showed a shorter tumour recurrence period(7.7 mo)than those with LCC(14.5 mo)(P<0.001),as well as shorter(OS)(58.4 mo for RCC patients;82.4 mo for LCC patients)(P=0.018).CONCLUSION RCC patients present more comorbidities,worse histological and molecular characteristics and a consequently higher probability of tumour recurrence,poor response to targeted therapy and shorter OS than LCC patients.展开更多
Gastrointestinal stromal tumors(GISTs)are rare neoplasms with an estimated incidence from 0.78 to 1-1.5 patients per 100000.They most commonly occur in the elderly during the eighth decade of life affecting predominan...Gastrointestinal stromal tumors(GISTs)are rare neoplasms with an estimated incidence from 0.78 to 1-1.5 patients per 100000.They most commonly occur in the elderly during the eighth decade of life affecting predominantly the stomach,but also the small intestine,the omentum,mesentery and rectosigmoid.The available treatments for GIST are associated with a significant rate of recurrent disease and adverse events.Thorough understanding of GIST’s pathophysiology and translation of this knowledge into novel regimens or drug repurposing is essential to counter this challenge.The present review summarizes the existing evidence about the role of angiogenesis in GIST’s development and progression and discusses its clinical underpinnings.展开更多
Hepatitis B virus(HBV) poses a significant challenge for both dialysis patients and kidney transplant recipients despite its decreasing rates, especially in developed countries. The best preventive method is vaccinati...Hepatitis B virus(HBV) poses a significant challenge for both dialysis patients and kidney transplant recipients despite its decreasing rates, especially in developed countries. The best preventive method is vaccination. Patients with chronic renal disease should ideally be vaccinated prior to dialysis, otherwise, reinforced vaccination practices and close antibody titer monitoring should be applied while on dialysis. HBV infected dialysis patients who are renal transplant candidates must be thoroughly examined by HBV-DNA, and liver enzyme testing and by liver biopsy. When needed, one must consider treating patients with tenofovir or entecavir rather than lamivudine. Depending on the cirrhosis stage, dialysis patients are eligible transplant recipients for either a combined kidney-liver procedure in the case of decompensated cirrhosis or a lone kidney transplantation since even compensated cirrhosis after sustained viral responders is no longer considered an absolute contraindication. Nucleoside analogues have led to improved transplantation outcomes with both long-term patient and graft survival rates nearing those of HBs Ag(-) recipients. Moreover, in the cases of immunized HBs Ag(-) potential recipients with concurrent prophylaxis, we are enabled today to safely use renal grafts from both HBs Ag(+) and HBs Ag(-)/antiHBc(+) donors. In so doing, we avoid unnecessary organ discarding. Universal prophylaxis with entecavir is recommended in HBV kidney recipients and should start perioperatively. One of the most important issues in HBV(+) kidney transplantation is the duration of antiviral prophylaxis. In the absence of robust data, it seems that prophylactic treatment may be discontinued in selected stable, low-risk recipients during maintenance immunosuppression and should be reintroduced when the immune status is altered. All immunosuppressive agents in kidney transplantation can be used in HBV(+) recipients. Immunosuppression is intimately associated with increased viral replication; thus it is important to minimize the total immunosuppression burden long term.展开更多
AIM:To identify genetic polymorphisms in the promoter region of the human base excision repair gene NEIL1 in gastric cancer patients.METHODS:The NEIL1 promoter region in DNA from 80 Japanese patients with gastric canc...AIM:To identify genetic polymorphisms in the promoter region of the human base excision repair gene NEIL1 in gastric cancer patients.METHODS:The NEIL1 promoter region in DNA from 80 Japanese patients with gastric cancer was searched for genetic polymorphisms by polymerase chain reaction-single-strand conformation polymorphism and subsequent sequencing analyses.RESULTS:Three novel genetic polymorphisms,i.e.c.-3769C>T,c.-3170T>G,and c.-2681TA[8],were identified in the NEIL1 promoter region at an allele frequency of 0.6%,9.4%,and 4.4%,respectively,in Japanese gastric cancer patients.CONCLUSION:Three NEIL1 promoter polymorphisms detected in this study may be of importance in gastric carcinogenesis.展开更多
A 67-year-old man visited our hospital with a history of continuous hematochezia leading to hemorrhagic shock.An abdominal computed tomography scan re-vealed a large mass in the ascending colon invading the duodenum a...A 67-year-old man visited our hospital with a history of continuous hematochezia leading to hemorrhagic shock.An abdominal computed tomography scan re-vealed a large mass in the ascending colon invading the duodenum and pancreatic head as well as extra-vasation of blood from the gastroduodenal artery(GDA) into the colon.Colonoscopy revealed an irregular ulcerative lesion and stenosis in the ascending colon.Therefore,right hemicolectomy combined with pylorus-preser ving pancreaticoduodenectomy was performed.Histologically,the tumor was classified as a moderately differentiated adenocarcinoma.Moreover,cancer cells were mainly located in the colon but had also invaded the duode-num and pancreas and involved the GDA.Immunohistochemically,the tumor cells were positive for cytokeratin(CK)20 and carcinoembryonic antigen(CEA)but not forCK7 and carbohydrate antigen(CA)19-9.The patient died 23 d after the surgery because he had another episode of arterial bleeding from the anastomosis site.Although En bloc resection of the tumor with pancreatico duodenectomy and colectomy performed for locally advanced colon cancer can ensure long-term survival,patients undergoing these procedures should be carefully monitored,particularly when the tumor involves the main artery.展开更多
Objective: To examine the expression and localisation of adrenomedullln in hum an coronary atherosclerotic lesions from patients with unstable angina(UAP) and stable angina(SAP), and to study the relation between adre...Objective: To examine the expression and localisation of adrenomedullln in hum an coronary atherosclerotic lesions from patients with unstable angina(UAP) and stable angina(SAP), and to study the relation between adrenomedullin expression and plaque instability. Design: A retrospective observational study. Patients: D irectional coronary atherectomy samples were obtained from 15 patients with UAP and 12 with SAP. Methods: The localisation of adrenomedullin was examined by imm unohistochemistry, and adrenomedullin mRNA expression was measured by quantitati ve polymerase chain reaction. Results: Adrenomedullin immunoreactivity was prefe rentially localised in macrophages, intimai smooth muscle cells, and proliferate d microvessels. The mean number of adrenomedullin positive cells in five high po wer fields(x 400) per specimen was higher in patients with UAP than in those wit h SAP (mean (SEM), 110(13) v 76 (7); p< 0.05); and the ratio of adrenomedullin p ositive to total cells was higher in patients with UAP (43.0 (2.2)%v 34.2 (2.0) %; p< 0.01). More adrenomedullin mRNA was expressed in the plaque of patients w ith UAP than in those with SAP (60.4 (16.9)%v 9.7 (3.3)%; p< 0.01). Conclusion s: The findings suggest that adrenomedullin is involved in the development of at herosclerosis and plaque instability in human coronary arteries, in an autocrine or paracrine manner.展开更多
Background:It remains unclear if the vascular and connective tissue structures of primary and metastatic tumors are intrinsically determined or whether these characteristics are defined by the host tissue.Therefore we...Background:It remains unclear if the vascular and connective tissue structures of primary and metastatic tumors are intrinsically determined or whether these characteristics are defined by the host tissue.Therefore we examined the microanatomical steps of vasculature and connective tissue development of C38 colon carcinoma in different tissues.Methods:Tumors produced in mice at five different locations(the cecal wall,skin,liver,lung,and brain)were ana-lyzed using fluorescent immunohistochemistry,electron microscopy and quantitative real-time polymerase chain reaction.Results:We found that in the cecal wall,skin,liver,and lung,resident fibroblasts differentiate into collagenous matrix-producing myofibroblasts at the tumor periphery.These activated fibroblasts together with the produced matrix were incorporated by the tumor.The connective tissue development culminated in the appearance of intratumoral tissue columns(centrally located single microvessels embedded in connective tissue and smooth muscle actin-expressing myofibroblasts surrounded by basement membrane).Conversely,in the brain(which lacks fibroblasts),C38 metasta-ses only induced the development of vascularized desmoplastic tissue columns when the growing tumor reached the fibroblast-containing meninges.Conclusions:Our data suggest that the desmoplastic host tissue response is induced by tumor-derived fibrogenic molecules acting on host tissue fibroblasts.We concluded that not only the host tissue characteristics but also the tumor-derived fibrogenic signals determine the vascular and connective tissue structure of tumors.展开更多
文摘Hepatocellular carcinoma(HCC) is the most frequent primary liver malignancy and the third cause of cancer-related death in the Western Countries. The well-established causes of HCC are chronic liver infections such as hepatitis B virus or chronic hepatitis C virus, nonalcoholic fatty liver disease, consumption of aflatoxins and tobacco smocking. Clinical presentation varies widely; patients can be asymptomatic while symptomatology extends from right upper abdominal quadrant paint and weight loss to obstructive jaundice and lethargy. Imaging is the first key and one of the most important aspects at all stages of diagnosis, therapy and follow-up of patients with HCC. The Barcelona Clinic Liver Cancer Staging System remains the most widely classification system used for HCC management guidelines. Up until now, HCC remains a challenge to early diagnose, and treat effectively; treating management is focused on hepatic resection, orthotopic liver transplantation, ablative therapies, chemoembolization and systemic therapies with cytotocix drugs, and targeted agents. This review article describes the current evidence on epidemiology, symptomatology, diagnosis and treatment of hepatocellular carcinoma.
基金Supported by the Grant-in-Aid for Scientific Research (C) from the Ministry of Culture and Science of Japan No. 16560645Grant-in-Aid for "Research for the Future" Program from The Japan Society for the Promotion of Science, No. JSPS-RFTF97I00201Supporting in Research Funds from The Japanese Foundation for Research and Promotion of Endoscopy, No. JFE-1997Shimidzu Immunology Foundation, 2000Tenri Foundation for Medical Research, 1997-2000Health and Labour Science Research Grants from the Japanese Ministry of Health, Labour and Welfare, and Research on Measures for Intractable Disease (Inflammatory Bowel Disease)a Grant from the "The 21st Century Center of Excellence (COE)" Program of the Ministry of Education, Culture, Sports, Science and Technology
文摘AIM： The role of the appendix has been highlighted in the pathogenesis of ulcerative colitis （UC）. The aims of this study were to elucidate the immuno-imbalances in the appendix of UC patients, and to clarify the role of the appendix in the development of UC. METHODS： Colonoscopic biopsy specimens of the appendix, transverse colon, and rectum were obtained from 86 patients with UC： active pancolitis （A-Pan; n = 15）, active letf-sided colitis （A-Lt; n = 25）, A-Lt with appendiceal involvement （A-Lt/Ap; n = 10）, inactive pancolitis （I-Pan; n = 14）, and inactive left-sided colitis （I-Lt; n = 22）, and from controls. In the isolated mucosal T cells, the CD4/CD8 ratio and proportion of activated CD4＋ T ceils were investigated, and compared with controls. RESULTS： in the appendix, the CD4/CD8 ratio significantly increased in A-Lt and A-Lt/Ap. The ratio in the appendix also tended to increase in A-Pan. In the rectum, the ratio significantly increased in all UC groups. In the appendix, the proportion of CD4＋CD69＋ （early activation antigen） T cells significantly increased in all UC groups. In the rectum, the proportion of CD4＋CD69＋ T cells significantly increased only in A-Pan. The proportion of CD4＋HLADR＋ （mature activation antigen） T cells significantly increased only in the rectum of A-Pan, but not in the otherareas of any groups. CONCLUSION： The increased CD4/CD8 ratio and predominant infiltration of CD4＋CD69＋ T cells in the appendix suggest that the appendix is a priming site in the development of UC.
文摘INTRODUCTION Since 1982,Helicobacter pylori(Hp) has been successfully isolated and cultured,and the fact many diseases such as gastritis,peptic ulcer,gastric carcinoma
文摘Tumors of the pancreas,the ampulla of Vater,and the extrahepatic and intrahepatic bile ducts have significant histological similarities due to the common embryonic origin of the pancreatobiliary system.This obviates the need for discovery of biomarkers with diagnostic and prognostic value for these tumors.Mucins,especially MUC-1,-2,-4 and-5AC,are important candidates for developing into such reliable biomarkers.Increased expression of MUC1 occurs in pancreatic ductal adenocarcinomas and is associated with increased degrees of dysplasia in pancreatic intraepithelial neoplasia(Pan IN).Positive expression of MUC2 in intraductal papillary mucinus neoplasms(IPMN) of the intestinal type indicates high potential progression to invasive carcinoma with de novo expression of MUC1,while absence of MUC2 expression in IPMNs of gastric type implies low potential to malignant evolution.De novo MUC4 expression correlates to the severity of dysplasia in Pan IN and is associated with a poor prognosis in patients with pancreatic ductal adenocarcinomas.In biliary intraepithelial neoplasia(Bil IN),increased expression of MUC1 is associated with higher degrees of dysplasia.Intrahepatic cholangiocarcinomas(ICC) are characterized by increased expression of all glycoforms of MUC1.Positive MUC2 expression in intraductal papillary neoplasm of the bile ducts(IPNB) of the intestinal type indicates high malignant potential with de novo expression of MUC1 in the invasive element.Absent MUC2 expression in any degree of Bil IN may prove useful in differentiating them from IPNB.De novo expression of MUC4 is associated with poor prognosis in patients with ICC or carcinoma of the extrahepatic bile ducts(EHBDC).High de novo expression of MUC5 AC is found in all degrees of Bil IN and all types of IPNB and ICC.The MUC5 AC is useful in the detection of neoplastic lesions of the bile duct at an early stage.Increased expression of mucin MUC1 in carcinoma of the ampulla of Vater associated with unfavorable behavior of the tumor,such as lymph node metastasis,infiltration of the pancreas and duodenum,advanced TNM classification and worse prognosis.Patients withintra-ampullary papillary-tubular neoplasm(IAPN) of the pancreatobiliary immunophenotype did not show MUC2,while those of the intestinal immunophenotype are MUC2 positive.The expression of MUC4 is associated with poor prognosis in patients with carcinoma of the ampulla of Vater favoring metastasis and making them resistant to apoptosis.Moreover,it appears that MUC4 positivity correlates with recurrence of the tumor.Expression of MUC5 AC is associated with the invasive potential of the tumor.
基金Grant-in-Aid 10670518(to Osamu Saitoh)for Scientific Research from the Ministry of Education,Science,Sports,and Culture,Japan
文摘INTRODUCTION Secondary amyloidosis is a rare but seriouscomplication of Crohn’s disease(CD).Theincidence of the association of secondaryamyloidosis in patients with CD has been reportedto be 0.5%-8% in Western countries.However,in Japan,the number of patients with CDcomplicated by amyloidosis is limited.Thecharacteristics of their clinical manifestations andthe incidence of association are uncertain.Therefore,we report herein a patient with
文摘BACKGROUND:Although invasive ductal adenocarcinoma of the pancreas(PDAC) manifests as a relatively uniform histomorphological feature of the pancreatobiliary type,it may be complicated by metaplastic changes and heterogeneous gastric and intestinal elements.This study aimed to investigate the complication rate and clinicopathological significance of such heterogeneous elements.METHODS:Fifty-nine patients who underwent resection of PDAC were examined in this study.Immunohistochemically,tumors showing high expression(>25%) of the intestinal-type(INT) marker CDX2 were classified as PDAC with INT.Those with high expression(>25%) of the gastric-type(GAS) marker MUC5AC were classified as PDAC with GAS,while those with high expression of both markers were classified as PDAC with INT/GAS.These patients were compared with those with PDAC of the negative group in which neither markers was highly expressed to examine their clinicopathological significance.RESULTS:In the 59 patients,31(52.5%) showed high CDX2 or MUC5AC expression.Twenty-eight patients(47.5%) belonged to a negative group,11(18.6%) to a PDAC with INT group,15(25.4%) to a PDAC with GAS group,and 5(8.5%) to a PDAC with INT/GAS group.No significant differences were observed for age,gender,size,localization,T classification,or prognosis among the four groups.Although the PDAC with GAS group had well differentiated types significantly more than the other groups,the rate of lymph node metastasis in this group was significantly higher(PDAC with GAS:73%;other groups:36%).CONCLUSION:Complications with heterogeneous elements are not uncommon in PDAC,and this should be considered during the diagnosis and treatment of PDAC along with histogenesis of the disease.
文摘The ventral quadrant of the tracheal epithelium of the hamster,about one fourth of tracheal mucosa, was denuded by a venous needle reformed.The stains were made with HE, PAS, and PAS-anti Brdu immunohis-tochemic technique. At the 0 h circumference cell number (CCN) was 927. 25.From 6 h post injured the viable cells changed in shapes and migrated from themargin to wound site. By 24 h the wound area was completely covered by a sin-gle layer of non-ciliated flattened cells, then an expotential increassing in cellregeneration occured in wound site by 48 h. The CCN had been restored to thelevel of control (1373), and the proliferative cell, composed of polygonal epi-dermoid metaplasia, 3～4 layers and reached a peak (338.8). The secretoryand ciliated cells appeared gradually from 72 h post injury, the epithelium re-stored to the normal epithelial architecture by one week post injury. In our pre-sent study either in control and non-injured epithelium or in all stages of woundsite about 70% of the Brdu positive cells contained small or confluent PAS posi-tive granules were observed. This fact indicated that secretory cells play a im-portant role in proliferation after mechanical injury and maintaining the normaltracheal pseudostratified epithelium.
文摘Colorectal cancer(CRC) constitutes the third most frequently reported malignancy in the male population and the second most common in women in the last two decades. Colon carcinogenesis is a complex, multifactorial event, resulting from genetic and epigenetic aberrations, the impact of environmental factors, as well as the disturbance of the gut microbial ecosystem. The relationship between the intestinal microbiome and carcinogenesis was relatively undervalued in the last decade. However, its remarkable effect on metabolic and immune functions on the host has been in the spotlight as of recent years. There is a strong relationship between gut microbiome dysbiosis, bowel pathogenicity and responsiveness to anti-cancer treatment;including immunotherapy. Modifications of bacteriome consistency are closely associated with the immunologic response to immunotherapeutic agents. This condition that implies the necessity of gut microbiome manipulation. Thus, creatingan optimal response for CRC patients to immunotherapeutic agents. In this paper, we will review the current literature observing how gut microbiota influence the response of immunotherapy on CRC patients.
基金Supported by Hungarian Research Fund(OTKA)(No.100904 to Kovalszky Iand No.105763 to Baghy K)
文摘Proteoglycans are a group of molecules that contain at least one glycosaminoglycan chain,such as a heparan,dermatan,chondroitin,or keratan sulfate,covalently attached to the protein core.These molecules arecategorized based on their structure,localization,and function,and can be found in the extracellular matrix,on the cell surface,and in the cytoplasm.Cell-surface heparan sulfate proteoglycans,such as syndecans,are the primary type present in healthy liver tissue.However,deterioration of the liver results in overproduction of other proteoglycan types.The purpose of this article is to provide a current summary of the most relevant data implicating proteoglycans in the development and progression of human and experimental liver cancer.A review of our work and other studies in the literature indicate that deterioration of liver function is accompanied by an increase in the amount of chondroitin sulfate proteoglycans.The alteration of proteoglycan composition interferes with the physiologic function of the liver on several levels.This article details and discusses the roles of syndecan-1,glypicans,agrin,perlecan,collagen XVIII/endostatin,endocan,serglycin,decorin,biglycan,asporin,fibromodulin,lumican,and versican in liver function.Specifically,glypicans,agrin,and versican play significant roles in the development of liver cancer.Conversely,the presence of decorin could potentially provide protective effects.
文摘Pancreatic cancer is one of the most aggressive human cancers,with more than 200 000 deaths worldwide every year.Despite recent efforts,conventional treatment approaches,such as surgery and classic chemotherapy,have only slightly improved patient outcomes.More effective and well-tolerated therapies are required to reverse the current poor prognosis of this type of neoplasm.Among new agents,histone deacetylase inhibitors (HDACIs) are now being tested.HDACIs have multiple biological effects related to acetylation of histones and many non-histone proteins that are involved in regulation of gene expression,apoptosis,cell cycle progression and angiogenesis.HDACIs induce cell cycle arrest and can activate the extrinsic and intrinsic pathways of apoptosis in different cancer cell lines.In the present review,the main mechanisms by which HDACIs act in pancreatic cancer cells in vitro,as well as their antiproliferative effects in animal models are presented.HDACIs constitute a promising treatment for pancreatic cancer with encouraging anti-tumor ef-fects,at well-tolerated doses.
基金Supported by the National Science Foundation of Hungary, No.OTKA 42674
文摘AIM： To characterize the alpha-fetoprotein （AFP） positive and negative hepatocellular carcinoma （HCC） samples. METHODS： Thirty-seven paraffin-embedded human HCC samples were analyzed by immunohistochemistry for the following antigens： AFP,β-catenin, p53, CD44, MSH-2, MLH-1, and HNF-4. The tumors were divided into two groups based on the AFP expression. The immunophenotypic data and important clinical parameters were studied between the two groups. RESULTS： Twenty-one of the thirty-seven examined HCCs were AFP positive. Seven with nudear p53 staining were AFP positive, while seven tumors with nuclear β-catenin staining were AFP negative. CD44 staining and high histological tumor grade were more frequent among the AFP-positive HCCs. The other immunophenotypical and dinical parameters did not show statistically significant difference in their distribution between the AFP positive and negative samples. CONCLUSION： AFP expression in HCC correlates with unfavorable prognostic factors, while nuclear β-catenin positivity is more common among the AFP-negative liver tumors. This observation supports the microarray data on in vivo human tumors.
文摘Despite reduction of hepatitis C prevalence after recognition of the virus and testing of blood products, hemodialysis(HD) patients still comprise a high risk group. The natural history of hepatitis C virus(HCV) infection in dialysis is not fully understood while the clinical outcome differs from that of the general population. HD patients show a milder liver disease with lower aminotransferase and viral levels depicted bymilder histological features on liver biopsy. Furthermore, the "silent" clinical course is consistent with a slower disease progression and a lower frequency of cirrhosis and hepatocellular carcinoma. Potential explanations for the "beneficial" impact of uremia and hemodialysis on chronic HCV infection are impaired immunosurveillance leading to a less aggressive host response to the virus and intradialytic release of "hepatoprotective" cytokines such as interferon(IFN)-α and hepatocyte growth factor. However, chronic hepatitis C is associated with a higher liver disease related cardiovascular and allcause mortality of HD patients. Therapy is indicated in selected patients groups including younger patients with low comorbidity burden and especially renal transplant candidates, preferably after performance of a liver biopsy. According to current recommendations, choice of treatment is IFN or pegylated interferon with a reported sustained viral response at 30%-40% and a withdrawal rate ranging from 17% to 30%. New data regarding combination therapy with low doses of ribavirin which provide higher standard variable rates and good safety results, offer another therapeutic option. The new protease inhibitors may be the future for HCV infected HD patients, though data are still lacking.
文摘BACKGROUND The differences in histopathology and molecular biology between right colon cancer(RCC)and left colon cancer(LCC)were first reported in the literature by Bufill in 1990.Since then,a large number of studies have confirmed their differences in epidemiology,clinical presentation,comorbidities and biological behaviours,which may be related to the difference in prognosis and overall survival(OS)between the two groups.AIM To investigate statistically significant differences between Greek patients with LCC and RCC.METHODS The present observational study included 144 patients diagnosed with colon cancer of any stage who received chemotherapy in a Greek tertiary oncology hospital during a 2.5-year period.Clinical information,comorbidities,histopathologic characteristics and molecular biomarkers were collected from the patients’medical records retrospectively,while administered chemotherapy regimens,targeted agents,progression-free survival(PFS)periods with first-and second-line chemotherapy and OS were recorded retroactively and prospectively.Data analysis was performed with the SPSS statistical package.RESULTS Eighty-six males and 58 females participated in the study.One hundred(69.4%)patients had a primary lesion in the left colon,and 44(30.6%)patients had a primary lesion in the right colon.Patients with RCC were more likely to display anaemia than patients with LCC[odds ratio(OR)=3.09],while LCC patients were more likely to develop rectal bleeding(OR=3.37)and a feeling of incomplete evacuation(OR=2.78)than RCC patients.Considering comorbidities,RCC patients were more likely to suffer from diabetes(OR=3.31)and coronary artery disease(P=0.056)than LCC patients.The mucinous differentiation rate was higher in the right-sided group than in the left-sided group(OR=4.49),as was the number of infiltrated lymph nodes(P=0.039),while the percentage of high-grade differentiation was higher in the group of patients with left-sided colon cancer than in RCC patients(OR=2.78).RAS wild-type patients who received anti-epidermal growth factor receptor(EGFR):Treatment experienced greater benefit(PFS:16.5 mo)than those who received anti-vascular endothelial growth factor treatment(PFS:13.7 mo)(P=0.05),while among RAS wild-type patients who received anti-EGFR treatment,LCC patients experienced greater benefit(PFS:15.8 mo)than the RCC subgroup(PFS:5.5 mo)in the first-line chemotherapy setting(P=0.034).BRAF-mutant patients had shorter PFS(9.3 mo)than BRAF wild-type patients(14.5 mo)(P=0.033).RCC patients showed a shorter tumour recurrence period(7.7 mo)than those with LCC(14.5 mo)(P<0.001),as well as shorter(OS)(58.4 mo for RCC patients;82.4 mo for LCC patients)(P=0.018).CONCLUSION RCC patients present more comorbidities,worse histological and molecular characteristics and a consequently higher probability of tumour recurrence,poor response to targeted therapy and shorter OS than LCC patients.
文摘Gastrointestinal stromal tumors(GISTs)are rare neoplasms with an estimated incidence from 0.78 to 1-1.5 patients per 100000.They most commonly occur in the elderly during the eighth decade of life affecting predominantly the stomach,but also the small intestine,the omentum,mesentery and rectosigmoid.The available treatments for GIST are associated with a significant rate of recurrent disease and adverse events.Thorough understanding of GIST’s pathophysiology and translation of this knowledge into novel regimens or drug repurposing is essential to counter this challenge.The present review summarizes the existing evidence about the role of angiogenesis in GIST’s development and progression and discusses its clinical underpinnings.
文摘Hepatitis B virus(HBV) poses a significant challenge for both dialysis patients and kidney transplant recipients despite its decreasing rates, especially in developed countries. The best preventive method is vaccination. Patients with chronic renal disease should ideally be vaccinated prior to dialysis, otherwise, reinforced vaccination practices and close antibody titer monitoring should be applied while on dialysis. HBV infected dialysis patients who are renal transplant candidates must be thoroughly examined by HBV-DNA, and liver enzyme testing and by liver biopsy. When needed, one must consider treating patients with tenofovir or entecavir rather than lamivudine. Depending on the cirrhosis stage, dialysis patients are eligible transplant recipients for either a combined kidney-liver procedure in the case of decompensated cirrhosis or a lone kidney transplantation since even compensated cirrhosis after sustained viral responders is no longer considered an absolute contraindication. Nucleoside analogues have led to improved transplantation outcomes with both long-term patient and graft survival rates nearing those of HBs Ag(-) recipients. Moreover, in the cases of immunized HBs Ag(-) potential recipients with concurrent prophylaxis, we are enabled today to safely use renal grafts from both HBs Ag(+) and HBs Ag(-)/antiHBc(+) donors. In so doing, we avoid unnecessary organ discarding. Universal prophylaxis with entecavir is recommended in HBV kidney recipients and should start perioperatively. One of the most important issues in HBV(+) kidney transplantation is the duration of antiviral prophylaxis. In the absence of robust data, it seems that prophylactic treatment may be discontinued in selected stable, low-risk recipients during maintenance immunosuppression and should be reintroduced when the immune status is altered. All immunosuppressive agents in kidney transplantation can be used in HBV(+) recipients. Immunosuppression is intimately associated with increased viral replication; thus it is important to minimize the total immunosuppression burden long term.
基金Supported by Grants-in-Aid from Ministry of Health, Labour and Welfare for the Comprehensive 10-Year Strategy for Cancer Control (19-19)Japan Society for the Promotion of Science for Scientific Research, No. 19790286+1 种基金Ministry of Education, Culture,Sports, Science and Technology for priority area, No. 20014007the 21st century COE program
文摘AIM:To identify genetic polymorphisms in the promoter region of the human base excision repair gene NEIL1 in gastric cancer patients.METHODS:The NEIL1 promoter region in DNA from 80 Japanese patients with gastric cancer was searched for genetic polymorphisms by polymerase chain reaction-single-strand conformation polymorphism and subsequent sequencing analyses.RESULTS:Three novel genetic polymorphisms,i.e.c.-3769C>T,c.-3170T>G,and c.-2681TA[8],were identified in the NEIL1 promoter region at an allele frequency of 0.6%,9.4%,and 4.4%,respectively,in Japanese gastric cancer patients.CONCLUSION:Three NEIL1 promoter polymorphisms detected in this study may be of importance in gastric carcinogenesis.
文摘A 67-year-old man visited our hospital with a history of continuous hematochezia leading to hemorrhagic shock.An abdominal computed tomography scan re-vealed a large mass in the ascending colon invading the duodenum and pancreatic head as well as extra-vasation of blood from the gastroduodenal artery(GDA) into the colon.Colonoscopy revealed an irregular ulcerative lesion and stenosis in the ascending colon.Therefore,right hemicolectomy combined with pylorus-preser ving pancreaticoduodenectomy was performed.Histologically,the tumor was classified as a moderately differentiated adenocarcinoma.Moreover,cancer cells were mainly located in the colon but had also invaded the duode-num and pancreas and involved the GDA.Immunohistochemically,the tumor cells were positive for cytokeratin(CK)20 and carcinoembryonic antigen(CEA)but not forCK7 and carbohydrate antigen(CA)19-9.The patient died 23 d after the surgery because he had another episode of arterial bleeding from the anastomosis site.Although En bloc resection of the tumor with pancreatico duodenectomy and colectomy performed for locally advanced colon cancer can ensure long-term survival,patients undergoing these procedures should be carefully monitored,particularly when the tumor involves the main artery.
文摘Objective: To examine the expression and localisation of adrenomedullln in hum an coronary atherosclerotic lesions from patients with unstable angina(UAP) and stable angina(SAP), and to study the relation between adrenomedullin expression and plaque instability. Design: A retrospective observational study. Patients: D irectional coronary atherectomy samples were obtained from 15 patients with UAP and 12 with SAP. Methods: The localisation of adrenomedullin was examined by imm unohistochemistry, and adrenomedullin mRNA expression was measured by quantitati ve polymerase chain reaction. Results: Adrenomedullin immunoreactivity was prefe rentially localised in macrophages, intimai smooth muscle cells, and proliferate d microvessels. The mean number of adrenomedullin positive cells in five high po wer fields(x 400) per specimen was higher in patients with UAP than in those wit h SAP (mean (SEM), 110(13) v 76 (7); p< 0.05); and the ratio of adrenomedullin p ositive to total cells was higher in patients with UAP (43.0 (2.2)%v 34.2 (2.0) %; p< 0.01). More adrenomedullin mRNA was expressed in the plaque of patients w ith UAP than in those with SAP (60.4 (16.9)%v 9.7 (3.3)%; p< 0.01). Conclusion s: The findings suggest that adrenomedullin is involved in the development of at herosclerosis and plaque instability in human coronary arteries, in an autocrine or paracrine manner.
基金KD is the recipient of the Bolyai fellowship of the Hungarian Academy of Sciences and received support from the National Excellence Program(TÁMOP 4.2.4.A/1-11-1-2012-0001)BD acknowledges support from the Hungarian NRDI Office(K109626,K108465,KNN121510 and SNN114490)+2 种基金SP and VL acknowledge support from the Hungarian NRDI Office(ANN125583)JT acknowledges support from the National Research,Development and Innovation Office(NKFIH116295)EB is the recipient of postdoctoral fellowship from the Hungarian Academy of Sciences.
文摘Background:It remains unclear if the vascular and connective tissue structures of primary and metastatic tumors are intrinsically determined or whether these characteristics are defined by the host tissue.Therefore we examined the microanatomical steps of vasculature and connective tissue development of C38 colon carcinoma in different tissues.Methods:Tumors produced in mice at five different locations(the cecal wall,skin,liver,lung,and brain)were ana-lyzed using fluorescent immunohistochemistry,electron microscopy and quantitative real-time polymerase chain reaction.Results:We found that in the cecal wall,skin,liver,and lung,resident fibroblasts differentiate into collagenous matrix-producing myofibroblasts at the tumor periphery.These activated fibroblasts together with the produced matrix were incorporated by the tumor.The connective tissue development culminated in the appearance of intratumoral tissue columns(centrally located single microvessels embedded in connective tissue and smooth muscle actin-expressing myofibroblasts surrounded by basement membrane).Conversely,in the brain(which lacks fibroblasts),C38 metasta-ses only induced the development of vascularized desmoplastic tissue columns when the growing tumor reached the fibroblast-containing meninges.Conclusions:Our data suggest that the desmoplastic host tissue response is induced by tumor-derived fibrogenic molecules acting on host tissue fibroblasts.We concluded that not only the host tissue characteristics but also the tumor-derived fibrogenic signals determine the vascular and connective tissue structure of tumors.
