Association of CD98, integrin β1, integrin β3 and Fak with the progression and liver metastases of colorectal cancer

CD98-mediated β1 and β3 integrins activation can induce Fak phosphorylation which eventually promotes cell survival, proliferation, and migration. We evaluated the expression of CD98, integrin β1, integrin β3 and Fak in 45 cases of matched colorectal cancer (CRC) and liver metastases as well as 35 cases of CRC without liver metastases.     

Prognostic role of integrin β1, E-cadherin, and rac1 expression in small cell lung cancer

Integrin β(1) mediates cellular adhesion to the extracellular matrix (ECM) and is correlated with highly invasive and metastatic behavior in small cell lung cancer (SCLC). E-cadherin (ECAD) is a calcium-dependent cell-cell adhesion receptor that restricts invasion of cells and reduces metastasis. Rac1 is involved in the regulation of the actin cytoskeleton, adhesion, migration, invasion, and tumor metastasis. The aim of this study was to examine integrin β(1) , ECAD and rac1 expression in SCLC and to analyze the prognostic value of these markers in patients with SCLC. We analyzed integrin β(1) , ECAD, and rac1 expression in 112 SCLC tissues by immunohistochemical staining. Correlative analyses between integrin β(1) , ECAD, and rac1 expression and cliniopathological factors were performed. A total of 65 patients had extensive disease (ED) (58%), and 47 had limited disease (LD) (42%). The median follow-up duration was 61 months (range: 14-117 months), and the median progression free survival (PFS) and overall survival (OS) were 6.1 months (range: 4.8-7.4 months) and 9.7 months (range: 8.1-11.3 months), respectively. The expression of integrin β(1) , ECAD, and rac1 protein was observed in 64, 73, and 99 of SCLC tissues, respectively. The correlative analyses between integrin β(1) , ECAD, or rac1 expression and various clinical parameters did not show any statistical significance. However, the ECAD expression was associated with OS in the entire cohort. In contrast, the expression of integrin β(1) and rac1 was not associated with PFS or OS. In a subgroup analysis, patients with less than two metastasis had significantly longer OS (p = 0.047) if their tumors expressed integrin β(1) compared to those without integrin β(1) expression. In addition, OS was longer for patients with ECAD positive tumors compared to those whose tumors did not express ECAD in males (p = 0.032) and patients who never smoked (p < 0.001). Multivariate analysis showed that LD (p = 0.004), overall response rate (p = 0.003), and expression of ECAD (p = 0.015) were the independent good prognostic factors for OS. LD (p = 0.024), overall response rate (p < 0.001), and less than two metastasis (p = 0.003) were prognostic factors for longer PFS. These results suggest that ECAD expression may be useful as a prognostic indicator in patients with SCLC.     

Prognostic value of transformer 2β expression in prostate cancer

Background: Deregulation of transformer 2β (Tra2β) has been implicated in several cancers. However, the role of Tra2β expression in prostate cancer (PCa) is unclear. Therefore, this study was to investigate the expression of Tra2β in PCa and evaluated its association with clinicopathological variables and prognosis. Methods: Thirty paired fresh PCa samples were analyzed for Tra2β expression by Western blot analysis. Immunohistochemistry (IHC) assay was performed in 160 PCa samples after radical prostatectomy and adjacent non-cancerous tissues. Tra2β protein expression was divided into high expression group and low expression group by IHC. We also investigated the association of Tra2β expression with clinical and pathologic parameters. Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the association between Tra2β protein expression and prognosis of PCa patients. Our results showed that Tra2β was significantly upregulated in PCa tissues by western blot and IHC. Results: Our data indicated that high expression of Tra2β was significantly associated with lymph node metastasis (P=0.002), clinical stage (P=0.015), preoperative prostate-specific antigen (P=0.003), Gleason score (P=0.001), and biochemical recurrence (P=0.021). High Tra2β expression was a significant predictor of poor biochemical recurrence free survival and overall survival both in univariate and multivariate analysis. Conclusion: We show that Tra2β was significantly upregulated in PCa patients after radical prostatectomy, and multivariate analysis confirmed Tra2β as an independent prognostic factor.     

Comparative evaluation of integrin α- and β-chain expression in colorectal carcinoma cell lines and in their tumours of origin

The integrin family consists of broadly expressed cell surface adhesion receptors, each member of which is composed of a non-covalently linked / heterodimer. Integrin receptors are involved in the interaction with matrix proteins and may contribute to invasion and metastasis of carcinomas. To examine the biological role integrins play in colorectal carcinoma we compared the expression of integrin - and -subunits in situ and in vitro. Eight newly established cell lines derived from immunohistochemically characterized colorectal carcinomas together with two sublines obtained after nude mouse passage and the commonly used colon carcinoma lines HT-29, SW480, SW620, and COLO 205 were investigated by immunocytochemistry and flow cytometry. The carcinomas in situ expressed 1-, 2-, 3-, 6-, v-and 1-subunits in variable amounts while being devoid of 4, 5 and 3. The individual integrin profile of the tumour in tissue was essentially maintained in vitro. However, a neo-expression of the 5 chain was found, together with an induction or increase in 1, 2, 3, v and 1 levels. No decrease in integrin subunit expression was observed. Standard-serum and serum-free medium revealed no striking differences in - and -chain expression in the cell lines HT-29 and COLO 205. In serum-free medium, SW480 showed a slight increase of 1 and 5 and a decrease of 3 and v while SW620 expressed more 1. We conclude that the great variability of adhesion receptor expression of the integrin family in colorectal carcinomas in situ is essentially maintained in vitro, although culture conditions which are only marginally influenced by serum factors unpredictably lead to some increase in expression or even induction of several integrin subunits.This work is dedicated to Prof. Wilhelm Doerr on the occasion of this 80th birthday     

Blockade of the renin–angiotensin system inhibits growth of colorectal cancer liver metastases in the regenerating liver

Partial hepatectomy (PH), the preferred option for selected patients with colorectal cancer liver metastases (CRCLM), is associated with 40–80 % tumor recurrence rates. Renin–angiotensin system (RAS) blockade inhibits tumor growth and has been suggested to improve liver regeneration. We documented the effect of RAS blockade on tumor growth and liver regeneration in a murine model. CRCLM induction followed by 70 % PH was performed on 78 CBA mice. Liver regeneration (days 2, 6) and CRCLM tumor load were measured by liver (and tumor) weights, percentage of CRCLM burden and tumor nodule count (days 16, 21). mRNA expression of the RAS components was characterised. Statistical analysis was performed using 2-independent sample T test or Mann–Whitney test (SPSS). Captopril did not impair liver regeneration. By day 21, Captopril decreased tumor burden (percentage of CRCLM in the liver) (48.7 ± 4.7 % control, 24.4 ± 6.2 Captopril; p = 0.008), tumor volume (1046.2 ± 200.2 mm³, 388.3 ± 150.4; p = 0.02), tumor nodule count per image field (181.1 ± 28.5, 68 ± 17.6; p = 0.005) and tumor angiogenesis (71.8 ± 6.4 vessels/mm², 43.1 ± 7.6; p = 0.015) compared to controls. Captopril enhanced tumor apoptosis (1 ± 0.2 %, 2.5 ± 0.7; p = 0.028). Liver regeneration and tumor development increased liver ACE levels. Blockade of the RAS effectively retarded CRCLM tumor growth at the late stage of tumor development within the regenerating liver without impeding liver regeneration following PH, via anti-angiogenesis and pro-tumor apoptosis. Captopril may be of therapeutic benefit in patients undergoing PH for CRCLM.     

In situ expression of β1, β3 and β4 integrin subunits in non-neoplastic endothelium and vascular tumours

Endothelial cells play an important role in adhesive interactions between circulating cells and extracellular matrix proteins. In vitro studies have shown that many of these processes are mediated by a superfamily of heterodimeric transmembrane glycoproteins called integrins. The distribution patterns of 1, 3 and 4 integrin subunits in endothelial cells (EC) in situ were examined immunohistochemically on serial forzen sections of a wide range of non-neoplastic tissues and of vascular tumours, both benign and malignant. Expression of the 1 subunit was a constitutive feature of EC. Among the 1-associated subunits, 5 and 6 were broadly distributed in EC, irrespective of vessel size and microenvironment. The 3 subunit displayed intermediate levels of expression with a slight preference for small vessel EC. Presence of 1 was confined to EC of capillaries and venules/small veins. Expression of 2 in EC was inconsistent. With rare exceptions, the 4 chain was absent in EC. The 3 and v subunits were expressed in most EC, though not always concomitantly. In contrast to the 1 chain, however, these integrin subunits were absent in EC of glomerular capillaries and were expressed variably in sinusoidal EC. The 4 chain was evenly present in the great majority of EC, except for those of large vessels. In vascular tumours, the patterns of 1 and 1 to 6 subunit expression generally corresponded to those found in their non-neoplastic counterparts. Expression of 3, v and 4 chains, however, decreased in neoplasia, especially in angiosarcomas. These data show that EC dispose of broad and at the same time differential repertoires of integrin subunits that presumably reflect vessel-type associated functional differences among these cells. In vascular tumours, the orthologous distribution patterns of 1 and 1 to 6 chains are conserved in most instances while the amounts of 3, v and 4 subunits expressed in EC tend to decrease in the course of malignant transformation.Dedicated to Prof. Dr. med. Dres. h.c. Wilhelm Doerr on the occasion of his 80th birthday     

Prognostic value of indeterminate IFN-γ release assay results in HIV-1 infection

In this prospective, longitudinal study on 948 HIV-1-infected patients, subjects with an indeterminate IFN-γ (gamma interferon) release assay (IGRA) result at baseline were at significantly higher risk of developing AIDS-defining manifestations other than tuberculosis (TB) irrespective of CD4(+) T cell count. Thus, in HIV-1-infected patients with advanced quantitative CD4(+) T cell depletion, an indeterminate IGRA might indicate an additional loss of global T cell function, warranting detailed clinical evaluation and careful follow-up.     

Histopathological evaluation of resected colorectal cancer liver metastases: what should be done?

Histological reporting of hepatic resections of colorectal liver metastases (CRLMs) is limited to confirmation of diagnosis and evaluation of resection margins. More exhaustive diagnostic reporting might be warranted. Here, we critically and systematically review the potentially important histological prognostic factors in CRLM. Histological features such as intrahepatic spread, resection margins, and tumour response to neoadjuvant chemotherapy have been defined. Intrahepatic spread (venous, lymphatic, bile duct and perineural invasion) was evaluated in a number of studies. Meta‐analysis demonstrated a clear correlation between 5‐year overall survival and both portal vein invasion (RR 1.8, 95% CI 1.3–2.5) and lymphatic invasion (RR 1.7, 95% CI 1.4–2.0). The impact of hepatic vein invasion and bile duct invasion on outcome is not clear. Perineural invasion was linked to survival in one study. Resection margin is an important prognostic factor; however, the significance of the width of negative margins remains controversial. Various studies have evaluated tumour response to neoadjuvant chemotherapy, but different grading systems were used, and definite recommendations cannot be made. In conclusion, with the high incidence of CRLM and the increase in the number of hepatic resections, we need well‐defined prognostic factors, studied in homogeneous patient populations, to optimize diagnostic work‐up. This review identifies several of these factors.     

Changes in the expression of syndecan-1 in the colorectal adenoma–carcinoma sequence

 Syndecan-1, a transmembrane heparan sulphate proteoglycan (HSPG), functions as a matrix receptor on the basal surface of epithelial cells. It also co-localizes with E-cadherin at the lateral cell surface where its function is uncertain. Tumour development in the large bowel is associated with loss of normal epithelial adhesion and altered patterns of expression of cell adhesion molecules, possibly including syndecan-1. To evaluate changes in syndecan-1 expression during the development of colorectal neoplasia, 59 adenomas and 20 carcinomas arising from adenomas were investigated by immunohistochemistry. The staining intensity and distribution of syndecan-1 and E-cadherin in sequential sections was examined, semi-quantified and compared. Staining of syndecan-1 and E-cadherin was uniform in normal colorectal epithelial cells, and located at the basolateral surface. No significant change was seen in either molecule in mildly or moderately dysplastic adenomas. A significant reduction in expression of both syndecan-1 and E-cadherin was seen in severely dysplastic epithelium as compared to moderate dysplasia (P=0.001 and P=0.004 respectively). Similarly, there was a significant reduction of both molecules in carcinomas compared with associated adenomas (syndecan-1 P=0.00003; E-cadherin P=0.002). In both cases the loss of syndecan-1 expression was more striking than that of E-cadherin. Previous in vitro studies have shown that epithelial cells made deficient in syndecan-1 cease to express E-cadherin, suggesting a causal association. Our results support these findings and indicate that disruption of cell-matrix adhesion is critical in colorectal carcinogenesis, probably preceding changes in the purely homotypic cell-cell adhesion mediated by E-cadherin. Received: 11 May 1998 / Accepted: 14 September 1998     

Prognostic value of serum HIF-1α change following transarterial chemoembolization in hepatocellular carcinoma

Clinical and Experimental Medicine - Transarterial chemoembolization (TACE) induces a change in serum HIF-1α level in patients with hepatocellular carcinoma (HCC). This study investigated the...     

The histopathologic report of surgically resected colorectal liver metastases: What is clinically relevant?

Colorectal carcinoma (CRC) is one of the most common malignancies and a major cause of cancer-related death worldwide. The liver is the most frequent site of metastatic spread, so that about half of the patients with CRC have or develop liver metastases (LM) during the clinical course of the disease. Colorectal LM can potentially be cured by surgery, but most patients still experience disease progression and recurrence after the surgical treatment. Prediction of a patient’s post-surgical clinical course is mainly based on clinical parameters or the histopathological features of the primary tumor, while little attention is given to the pathological characteristics of the LM. In this paper, we review the prognostic relevance of the gross and microscopic pathological features observed in surgically resected LM and propose which information should be included in the histopathological report to guide surgeons and oncologists for the subsequent therapeutic management.     

Elevated expression of transforming growth factor β3 in carbon tetrachloride-treated rat liver and involvement of retinoid signaling

Transforming growth factor (TGF) β is a pro-fibrotic cytokine. While three isoforms (TGF-β1, 2 and 3) are known, the functional differences between them are obscure. To investigate the roles of TGF-β isoforms during liver fibrogenesis, male Wistar rats were administrated carbon tetrachloride (CCl4) subcutaneously twice a week for two months. Livers were excised and sectioned for histochemical examinations. These livers were also used to quantitate the expression of genes associated with fibrogenesis, including TGF-β isoforms, as well as those associated with retinoid metabolism. Expression levels of Tgfb1 and Tgfb3 were up-regulated in CCl4-treated rat livers while that of Tgfb2 was not changed. The mRNAs for lecithin-retinol acyltransferase (Lrat) and retinoic acid hydroxylase, Cyp26a1, were also elevated. By immunohistochemical staining, TGF-β3 protein was found to be localized mainly in liver parenchymal cells (hepatocytes). These results indicate that retinoid mobilization likely takes place within the rat's liver following CCl4 treatment, and suggest the possibility that the expression of Tgfb mRNA is regulated by retinoic acid receptors. Reporter analyses of a region of the Tgfb3 gene were performed using the rat liver parenchymal cell line, RLC-16, and a positively responsive region was identified within its intron.     

Expression and clinical significance of CD151 and integrin α3β1 in colorectal tumors

目的:探讨CD151和整合素α3β1在直肠腺瘤及结直肠腺癌组织中的表达及其与临床各个病理因素之间的关系,并且研究两者的相关性.方法:应用免疫组织化学双染方法对正常结直肠黏膜、结直肠腺瘤及结直肠腺癌组织各120例进行CD151和整合素α3β1检测,并进行Kaplan-Meier生存分析.采用Spearman等级相关分析CD151和整合素αβ1之间的相关性.结果:CD151结直肠正常黏膜、腺瘤、腺癌组织的阳性率分别为21.7％、52.5％、72％,腺瘤和腺癌组织分别与正常黏膜比较均具有统计学意义.整合素α3β1在结直肠正常黏膜、腺瘤、腺癌组织的阳性率分别为34.2％、55％、70％,腺瘤和腺癌组织分别与正常黏膜比较均具有统计学意义.在结直肠腺癌中,CD151和整合素α3β1的表达与患者年龄、性别和肿瘤的部位、大小无相关性,与肿瘤的分化程度、浸润深度、淋巴结转移及Duke's分期有关.CD151和整合素α3β1在大肠正常黏膜、腺瘤及腺癌组织中的表达经双变量相关分析,表达呈正相关.从图的Kaplan-Meier生存曲线及Log-Rank检验可知,CD151+、α3β1+、CD151+α3β1+与大肠癌患者5年生存期密切相关,是影响大肠癌预后的因素.结论:CD151和整合素α3β1在大肠癌的表达密切相关,提示CD151与整合素α3β1复合物存在于大肠癌,其表达对预后产生明显的影响.CD151与整合素α3β1联合表达是临床预后判断的可靠指标.     

Conversion of β-alanine in vivo and in isolated liver tissue

Summary -alanine was incubated with chopped liver tissue of rats in oxygen for 160 minutes at 37°C. It was established that a certain part of added -alanine (about 12%) disappears, causing an excessive production of urea and of a small quantity of -alanine.In parenteral administration of -alanine an increased urinary excretion of this amino acid is observed in B₆-deficient rats in which the process of -alanine transformation is disturbed.     

Prognostic value of immunocytochemical determination of parathyroid hormone-related peptide expression in cells of mammary ductal carcinoma. Analysis of 7 years of the disease course

Parathyroid hormone-related peptide (PTHrP) participates in the development of humoral hypercalcaemia of malignancy. The peptide is thought to affect growth and differentiation of normal and neoplastic cells. The present study aimed at evaluation of the relationship between survival time and development of distant metastases in patients with ductal mammary carcinoma on the one hand and PTHrP expression on the other. Immunocytochemical reactions using mouse monoclonal (clone 212-10.7) anti-PTHrP (38-64) antibodies were performed in paraffin sections originating from 47 patients with ductal mammary carcinoma. Expression of the protein was quantified employing a scale, considering the number of positive cells and intensity of the reaction (immunoreactive score, IRS). Survival time of the patients, determined during the course of a 7-year observation was also analysed. The obtained results demonstrated a relationship between intensity of PTHrP expression and the survival time. Patients with high expression of PTHrP (IRS>6) manifested longer survival than patients with lower PTHrP expression (IRS< or =6; Cox'es F test, P<0.05). Moreover, in the group with the lower PTHrP expression, a negative relationship was detected between expression of the protein and the survival time (Cox'es model, P<0.05). No relationship was detected between PTHrP expression and the development of distant metastases.