Marker For Cancer Progression Research Articles

Tumor expression, plasma levels and genetic polymorphisms of the coagulation inhibitor TFPI are associated with clinicopathological parameters and survival in breast cancer, in contrast to the coagulation initiator TF.

IntroductionHypercoagulability in malignancy increases the risk of thrombosis, but is also involved in cancer progression. Experimental studies suggest that tissue factor (TF) and tissue factor pathway inhibitor (TFPI) are involved in cancer biology as a tumor- promoter and suppressor, respectively, but the clinical significance is less clear. Here, we aimed to investigate the clinical relevance of TF and TFPI genetic and phenotypic diversity in breast cancer.MethodsThe relationship between tumor messenger RNA (mRNA) expression and plasma levels of TF and TFPI (α and β), tagging single nucleotide polymorphisms (tagSNPs) in F3 (TF) (n = 6) and TFPI (n = 18), and clinicopathological characteristics and molecular tumor subtypes were explored in 152 treatment naive breast cancer patients. The effect of tumor expressed TF and TFPIα and TFPIβ on survival was investigated in a merged breast cancer dataset of 1881 patients.ResultsProgesterone receptor negative patients had higher mRNA expression of total TFPI (α + β) (P = 0.021) and TFPIβ (P = 0.014) in tumors. TF mRNA expression was decreased in grade 3 tumors (P = 0.003). In plasma, total TFPI levels were decreased in patients with larger tumors (P = 0.013). SNP haplotypes of TFPI, but not TF, were associated with specific clinicopathological characteristics like tumor size (odds ratio (OR) 3.14, P = 0.004), triple negativity (OR 2.4, P = 0.004), lymph node spread (OR 3.34, P = 0.006), and basal-like (OR 2.3, P = 0.011) and luminal B (OR 3.5, P = 0.005) molecular tumor subtypes. Increased expression levels of TFPIα and TFPIβ in breast tumors were associated with better outcome in all tumor subtypes combined (P = 0.007 and P = 0.005) and in multiple subgroups, including lymph node positive subjects (P = 0.006 and P = 0.034).ConclusionsThis study indicates that genetic and phenotypic variation of both TFPIα and TFPIβ, more than TF, are markers of cancer progression. Together with the previously demonstrated tumor suppressor effects of TFPI, the beneficial effect of tumor expressed TFPI on survival, renders TFPI as a potential anticancer agent, and the clinical significance of TFPI in cancer deserves further investigation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0548-5) contains supplementary material, which is available to authorized users.

Nuclear osteopontin-c is a prognostic breast cancer marker.

Background:Although Osteopontin has been known as a marker for cancer progression, the elevated production of this cytokine is not specific for cancer. We have identified the splice variant Osteopontin-c as being absent from healthy tissue but associated with about 75% of breast cancer cases. However, in previous studies of Osteopontin-c, follow-up information was not available.Methods:Here we have analysed 671 patients, comprising a cohort of 291 paraffin blocks plus a population-based case-control study of 380 arrayed breast tumor tissues.Results:We find that high staining intensity of nuclear Osteopontin-c is strongly associated with mortality in patients with early breast cancer. Cytosolic staining for exon 4, reflective of Osteopontin-a and -b also predicts poor outcome. By contrast, total Osteopontin does not correlate with prognosis. These diverse assessments of Osteopontin also do not correlate with each other, suggesting distinct expression patterns for the variant forms. Consistent with its role in tumor progression, not tumor initiation, Osteopontin-c is not correlated with proliferation markers (Ki-67, cyclin A, cyclin B, cyclin E and cyclin D), neither is it correlated with ER, PR or HER2.Conclusions:The addition of Osteopontin-c immunohistochemistry to standard pathology work-ups may have prognostic benefit in early breast cancer diagnosis.

Elevated expression of IMPDH2 is associated with progression of kidney and bladder cancer.

Novel molecular markers for cancer progression are valuable for the diagnosis and evaluation of treatment efficacies of the diseases. Expression of inosine 5'-monophosphate dehydrogenase type II (IMPDH2), a rate-limiting enzyme in the de novo guanine nucleotide biosynthesis, is up-regulated in various neoplasms, including prostate cancer and patient serum. However, whether IMPDH2 can serve as a biomarker for other urologic cancers is unknown. Paired patient tissue macroarrays were analyzed by immunohistochemistry, the IMPDH2 protein expression in these tissues was quantitated and expressed as immunoreactivity scores. Compared with non-cancerous tissues, IMPDH2 protein expression levels were significantly upregulated in kidney and bladder cancer, but no difference in testis cancer. In addition, expression of IMPDH2 was not associated with the disease clinical stages and pathological features. The findings suggest that overexpressed IMPDH2 can be used as a biomarker for kidney and bladder cancer diagnosis and is a potential therapeutic target for the diseases.

Development of an actionable test for risk stratification of oral premalignant lesions

Early detection of at-risk oral lesions followed by effective intervention is the key to control oral cancer. Both retrospective and prospective cohorts from our group have shown that loss of heterozygosity (LOH) at 9p21 is a risk marker for cancer progression. However, the technique used is radio-isotope-based electrophoresis (RE) with costly, labor-intensive and time barriers. The purpose of the study is to develop a comparable lab-friendly actionable test using fluorescence- based capillary electrophoresis (FCE).

Clinical implications of MTA proteins in human cancer.

Metastasis-associated gene or metastasis tumor antigen 1 (MTA1) is a new member of cancer progression-related gene family. It was first identified in rat mammary adenocarcinoma and later recognized as an important constituent of nucleosomal remodeling complex (NuRD), displaying dual regulatory functions as a co-repressor and co-activator for a large number of genes. Chromatin remodelers are ATP-dependent multi-protein chromatin modifying machines. These complexes alter the nucleosome positioning regulating the accessibility of genomic DNA to various transcription factors and thus modulate eukaryotic gene transcription. Since its identification two decades ago, MTA1 has been reported to be overexpressed in many cancers. Moreover, its overexpression has also been correlated with transformation and tumor progression. Furthermore, MTA1 has been shown to modulate the response of several tumor suppressor genes like p53 and oncogenes like c-myc. Taken together, current literature suggests that MTA proteins, especially MTA1, act as a master co-regulatory molecule involved in the carcinogenesis and progression of various malignant tumors. The primary focus of this review is to provide an overview of the MTA proteins with special emphasis on its role in cancer and use as a marker for cancer progression and potential target for therapy.

Antireflux surgery for dysplastic Barrett's esophagus.

Nearly a decade ago I came home from DDW with scars on my ego, having been scolded by gastroenterologists for touting the ability of laparoscopic fundoplication to protect patients with Barrett’s esophagus from the ravages of esophageal cancer. As high volume laparoscopic antireflux surgeons with many Barrett’s patients treated, quite a number of us (Hunter, Pellegrini, Peters, Oberg, and others) had observed and reported extremely low rates of cancer development in our Barrett’s patients under annual surveillance after fundoplication, rates much lower than medical surveillance studies of patients on PPIs. As a result of this intellectual dissonance, I challenged Eugene Chang, an extremely bright surgical resident at our institution to answer the question: Does laparoscopic fundoplication protect against cancer in patients with Barrett’s esophagus? The result was a very well performed systematic review of the literature, with a mixed message [1]. All in, Barrett’s patients were less likely to develop cancer after fundoplication, BUT the literature was dominated by case series—such as ours—where selection bias may have favored younger, healthier patients with short segment Barrett’s, excellent compliance with care recommendations, and less endstage physiology (strictures, motor disorders, giant hernias, etc.). When we looked at RCT’s (1) and case-controlled series (4) we could not demonstrate a difference. It was no longer clear that fundoplication prevented the progression of Barrett’s esophagus to cancer. So with my tail between my legs, I changed my tune… but only a little. This review by Allaix and Patti has covered all the bases, found all the relevant studies, and summarized them well. While we may not be able to PROVE that fundoplication prevents cancer, we can show that the factors that cause cancer (unrelenting reflux by acid and bile) are better treated with a functional valve (fundoplication) than with PPIs. PPIs rarely normalize esophageal acid exposure in Barrett’s patients. Because GERD patients often have symptom reduction when Barrett’s metaplasia develops, the only way to insure that Barrett’s patients on PPI have adequate acid exposure reduction is to perform esophageal pH studies while the patient is on a PPI. Even if PPI dosage is elevated to ‘‘nuclear’’ levels and esophageal acid is eliminated, there is still bile… and other refluxate… In addition, surrogate markers for cancer progression in Barrett’s esophagus are down regulated after fundoplication, suggesting that pathways favoring proliferation and cell dysregulation respond to the elimination of bile and acid. Lastly, the data seem pretty reproducible that a failed fundoplication puts a Barrett’s patient at higher risk for esophageal cancer. So maybe fundoplication really does make a difference? With all this background, the question addressed in this paper is ‘‘what about dysplastic Barrett’s?’’ Here the data gets a little slim. Low grade dysplasia (LGD) is the ‘slipperiest’ diagnosis in esophageal disease. When looking at the same slide, pathologists will frequently disagree over the diagnosis of LGD. Subsequent endoscopies in the same patient, with or without treatment, will frequently demonstrate different findings (no dysplasia, high grade dysplasia (HGD), or intramucosal cancer). So it’s hard to know what to do with LGD. At one time, we thought it should be treated with radiofrequency ablation (RFA) and pH control (fundoplication or PPI), but now the evanescent nature of LGD drives us more toward continued surveillance and pH control only.

Abstract 1107: Tumor microenvironment based modulation of thyroid cancer phenotype

Abstract Inflammation plays a pivotal role in the progression of solid malignant tumor with studies showing that the presence of specific inflammatory-immune cells, such as macrophages, at the tumor site leads to poor prognosis. M1 polarized macrophages secrete pro-inflammatory chemokines and cytokines which induce an epithelial to mesenchymal transition (EMT) in tumor cells; a process where epithelial cells acquire mesenchymal traits, thus facilitating tissue infiltration and consequent metastasis. EMT as a marker of cancer progression is understudied in thyroid cancer. In our present study, we evaluated the crosstalk between the macrophages and the epithelial cells in the thyroid tumor microenvironment with the use of an in vitro model system consisting of an immortalized thyroid cell line (Nthy-ori 3-1), three papillary cancer cell lines (BCPAP, 8505C and TPC-1) and one follicular cancer cell line (CGTHW-1). We observed the halt in proliferation of the thyroid cancer cells as the epithelial cells differentiate into mesenchymal cells under the influence of activated macrophage conditioned media. We also observed a statistically significant (p<0.05) upregulation of migration and invasion of thyroid tumor cells in presence of macrophage conditioned media. Using nuclear and cytoplasmic extracts from the thyroid cancer cell lines, we observed that EMT markers including E-cadherin, β-catenin, vimentin, NFk-B, snail, slug and twist are modulated in response to activated macrophage conditioned media. Downregulation of E-cadherin, required for maintenance of stable junction and β-catenin essential for cell-cell adhesion was noticed in response to macrophage conditioned media. Transcription factors like NFk-B, snail and slug were translocated to the nucleus, which is indicative of the initiation of EMT. Our data provides evidence that macrophage secreted proteins play a crucial role in epithelial-mesenchymal transition in thyroid tumor advancement and metastasis. We have successfully identified some significant markers including transcription factors such as NFk-B, slug, twist and snail that play a critical role in the induction of epithelial to mesenchymal transition in thyroid cancer. These findings will allow for the possible development of targeted therapy designed at inhibiting EMT and subsequent suppression of thyroid cancer metastasis and dissemination. Citation Format: Neha Y. Tuli, Jonathan Cabin, Robert Suriano, Robert Bednarczyk, Elyse Hanly, Jan Geliebter, Edward Shin, Raj K. Tiwari. Tumor microenvironment based modulation of thyroid cancer phenotype. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1107. doi:10.1158/1538-7445.AM2014-1107

HDGF: a novel jack-of-all-trades in cancer.

HDGF is an important regulator of a broad range of cancer cell activities and plays important roles in cancer cell transformation, apoptosis, angiogenesis and metastasis. Such a divergent influence of HDGF on cancer cell activities derives from its multiple inter- and sub-cellular localizations where it interacts with a range of different binding partners. Interestingly, high levels of HDGF could be detected in patients' serum of some cancers. This review is focused on the role of HDGF in tumorigenesis and metastasis, and provides insight for application in clinical cancer therapy as well as its clinical implications as a prognostic marker in cancer progression.

183: From ERa66 to ERa36: a new predictive marker for cancer progression and therapeutic response in breast tumors?

183: From ERa66 to ERa36: a new predictive marker for cancer progression and therapeutic response in breast tumors?

TRPM7 involvement in cancer: a potential prognostic factor.

Calcium (Ca(2+)) and magnesium (Mg(2+)) are important metal elements that regulate a variety of cellular processes such as proliferation, migration, and apoptosis, in cancer cells. Among the ionic channels mediating intracellular entry, the transient receptor potential melastatin type 7 (TRPM7) channel is of particular interest, it being a non-selective, cationic channel mediating both Ca(2+) and Mg(2+) influx. TRPM7 is highly expressed in a number of human cancer tissues and cell lines. In this review, we summarise current knowledge on the physiological role of the dual function TRPM7 chanzyme, the potential application of TRPM7 as a diagnostic and prognostic marker of cancer progression with respect to clinical and pathological characteristics, and the molecular mechanisms implicated in cancerogenesis that specifically involve Ca(2+) and Mg(2+) influx through TRPM7 or kinase activity and interaction with cytoskeletal proteins.

On-chip lectin microarray for glycoprofiling of different gastritis types and gastric cancer.

An on-chip lectin microarray based glycomic approach is employed to identify glyco markers for different gastritis and gastric cancer. Changes in protein glycosylation have impact on biological function and carcinogenesis. These altered glycosylation patterns in serum proteins and membrane proteins of tumor cells can be unique markers of cancer progression and hence have been exploited to diagnose various stages of cancer through lectin microarray technology. In the present work, we aimed to study the alteration of glycan structure itself in different stages of gastritis and gastric cancer thoroughly. In order to perform the study from both serum and tissue glycoproteins in an efficient and high-throughput manner, we indigenously developed and employed lectin microarray integrated on a microfluidic lab-on-a-chip platform. We analyzed serum and gastric biopsy samples from 8 normal, 15 chronic Type-B gastritis, 10 chronic Type-C gastritis, and 6 gastric adenocarcinoma patients and found that the glycoprofile obtained from tissue samples was more distinctive than that of the sera samples. We were able to establish signature glycoprofile for the three disease groups, that were absent in healthy normal individuals. In addition, our findings elucidated certain novel signature glycan expression in chronic gastritis and gastric cancer. In silico analysis showed that glycoprofile of chronic gastritis and gastric adenocarcinoma formed close clusters, confirming the previously hypothesized linkage between them. This signature can be explored further as gastric cancer marker to develop novel analytical tools and obtain in-depth understanding of the disease prognosis.

Apelin beyond kidney failure and hyponatremia: a useful biomarker for cancer disease progression evaluation

Apelin regulates angiogenesis, stimulating endothelial cell proliferation and migration. It is upregulated during tumor angiogenesis, and its overexpression was reported to increase tumor growth. Furthermore, apelin controls vasopressin release and body fluid homeostasis. The aim of this study was to examine the correlations between apelin expression and clinical outcomes in oncologic patients, such as cancer disease progression and patient's survival. Apelin levels were evaluated in a cohort of 95 patients affected by different varieties of cancer. Partial remission and stable disease were assigned to the 'no progression' group, comparing it with the progressor group. Patients were followed up for 2 years. Receiver operating characteristics analysis was employed for identifying the progression of the oncologic disease and Kaplan-Meier curves assessed the survival. Adjusted risk estimates for progression endpoint were calculated using Cox proportional hazard regression analysis. Oncologic patients had higher apelin levels compared with healthy subjects, and apelin was closely related to the stages of the disease. In the hyponatremia group, apelin values were significantly higher than patients with eunatremia. After the follow-up of 24 months, 41 patients (43%) reached the endpoint. Progressor subjects presented significantly increased apelin values at baseline compared with non-progressor. Univariate followed by multivariate Cox proportional hazard regression analysis showed that apelin predicted cancer progression independently of other potential confounders. In patients with cancer, apelin closely reflects the stage of the disease and represents a strong and independent risk marker for cancer progression.

Soluble Carcinoembryonic Antigen Activates Endothelial Cells and Tumor Angiogenesis

Carcinoembryonic antigen (CEA, CD66e, CEACAM-5) is a cell-surface-bound glycoprotein overexpressed and released by many solid tumors that has an autocrine function in cancer cell survival and differentiation. Soluble CEA released by tumors is present in the circulation of patients with cancer, where it is used as a marker for cancer progression, but whether this form of CEA exerts any effects in the tumor microenvironment is unknown. Here, we present evidence that soluble CEA is sufficient to induce proangiogenic endothelial cell behaviors, including adhesion, spreading, proliferation, and migration in vitro and tumor microvascularization in vivo. CEA-induced activation of endothelial cells was dependent on integrin β-3 signals that activate the focal-adhesion kinase and c-Src kinase and their downstream MAP-ERK kinase/extracellular signal regulated kinase and phosphoinositide 3-kinase/Akt effector pathways. Notably, while interference with VEGF signaling had no effect on CEA-induced endothelial cell activation, downregulation with the CEA receptor in endothelial cells attenuated CEA-induced signaling and tumor angiogenesis. Corroborating these results clinically, we found that tumor microvascularization was higher in patients with colorectal cancer exhibiting higher serum levels of soluble CEA. Together, our results elucidate a novel function for soluble CEA in tumor angiogenesis.

Stathmin expression in endometrial hyperplasia: A potential marker for cancer progression

Objective: Stathmin (STMN) expression has been identified as a marker for PI3Kiniase activation and poor prognosis in endometrial cancer. PTEN and the PI3Kinase pathway have been associated with endometrial cancer progression. There continues to be a need to identify prognostic indicators for endometrial hyperplasia progression to endometrial carcinoma. Our objective was to identify whether STMN expression could be used as an indicator of aggressive endometrial hyperplasia.

Age-Specific Gene Expression Signatures for Breast Tumors and Cross-Species Conserved Potential Cancer Progression Markers in Young Women

Breast cancer in young women is more aggressive with a poorer prognosis and overall survival compared to older women diagnosed with the disease. Despite recent research, the underlying biology and molecular alterations that drive the aggressive nature of breast tumors associated with breast cancer in young women have yet to be elucidated. In this study, we performed transcriptomic profile and network analyses of breast tumors arising in Middle Eastern women to identify age-specific gene signatures. Moreover, we studied molecular alterations associated with cancer progression in young women using cross-species comparative genomics approach coupled with copy number alterations (CNA) associated with breast cancers from independent studies. We identified 63 genes specific to tumors in young women that showed alterations distinct from two age cohorts of older women. The network analyses revealed potential critical regulatory roles for Myc, PI3K/Akt, NF-κB, and IL-1 in disease characteristics of breast tumors arising in young women. Cross-species comparative genomics analysis of progression from pre-invasive ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) revealed 16 genes with concomitant genomic alterations, CCNB2, UBE2C, TOP2A, CEP55, TPX2, BIRC5, KIAA0101, SHCBP1, UBE2T, PTTG1, NUSAP1, DEPDC1, HELLS, CCNB1, KIF4A, and RRM2, that may be involved in tumorigenesis and in the processes of invasion and progression of disease. Array findings were validated using qRT-PCR, immunohistochemistry, and extensive in silico analyses of independently performed microarray datasets. To our knowledge, this study provides the first comprehensive genomic analysis of breast cancer in Middle Eastern women in age-specific cohorts and potential markers for cancer progression in young women. Our data demonstrate that cancer appearing in young women contain distinct biological characteristics and deregulated signaling pathways. Moreover, our integrative genomic and cross-species analysis may provide robust biomarkers for the detection of disease progression in young women, and lead to more effective treatment strategies.

Chromatin patterns associated with lung adenocarcinoma progression

The development and progression of lung adenocarcinoma, one of the most common cancers, is driven by the interplay of genetic and epigenetic changes and the role of chromatin structure in malignant transformation remains poorly understood. We used systematic nucleosome distribution and chromatin accessibility microarray mapping platforms to analyze the genome-wide chromatin structure from normal tissues and from primary lung adenocarcinoma of different grades and stages. We identified chromatin-based patterns across different patients with lung adenocarcinoma of different cancer grade and stage. Low-grade cancers had nucleosome distributions very different compared with the corresponding normal tissue but had nearly identical chromatin accessibility. Conversely, nucleosome distributions of high-grade cancers showed few differences. Substantial disruptions in chromosomal accessibility were seen in a patient with a high-grade and high-stage tumor. These data imply that chromatin structure changes during the progression of lung adenocarcinoma. We have therefore developed a model in which low-grade lung adenocarcinomas are linked to changes in nucleosome distributions, whereas higher-grade tumors are linked to large-scale chromosomal changes. These results provide a foundation for the development of a comprehensive framework linking the general and locus-specific roles of chromatin structure to lung cancer progression. We propose that this strategy has the potential to identify a new class of chromatin-based diagnostic, prognostic and therapeutic markers in cancer progression.

Control of the Human Osteopontin Promoter by ERRα in Colorectal Cancer

Colorectal cancer is the second leading cause of death from cancer. Osteopontin (OPN) is a component of tumor extracellular matrix identified as a key marker of cancer progression. The estrogen-related receptor α (ERRα) has been implicated in endocrine-related cancer development and progression, possibly through modulation of cellular energy metabolism. Previous reports that ERRα regulates OPN expression in bone prompted us to investigate whether ERRα controls OPN expression in human colorectal cancer. Using a tissue microarray containing 83 tumor-normal tissue pairs of colorectal cancer samples, we found that tumor epithelial cells displayed higher staining for ERRα than normal mucosa, in correlation with elevated OPN expression. In addition, knocking down endogenous ERRα led to reduced OPN expression in HT29 colon cancer cells. Promoter analysis, inhibition of ERRα activity, and expression and mutation of potential ERRα response elements in the proximal promoter of human OPN showed that ERRα and its obligate co-activator, peroxisome proliferator-activated receptor γ co-activator-1 α, positively control human OPN promoter activity. Furthermore, chromatin immunoprecipitation experiments confirmed in vivo occupancy of the OPN promoter by ERRα in HT29 cells, suggesting that OPN is a direct target of ERRα in colorectal cancer. These findings suggest an additional mechanism by which ERRα participates in the development and progression of colorectal cancer, further supporting the relevance of targeting ERRα with antagonists as anticancer agents.

Negative transcriptional control of ERBB2 gene by MBP-1 and HDAC1: diagnostic implications in breast cancer

BackgroundThe human ERBB2 gene is frequently amplified in breast tumors, and its high expression is associated with poor prognosis. We previously reported a significant inverse correlation between Myc promoter-binding protein-1 (MBP-1) and ERBB2 expression in primary breast invasive ductal carcinoma (IDC). MBP-1 is a transcriptional repressor of the c-MYC gene that acts by binding to the P2 promoter; only one other direct target of MBP-1, the COX2 gene, has been identified so far.MethodsTo gain new insights into the functional relationship linking MBP-1 and ERBB2 in breast cancer, we have investigated the effects of MBP-1 expression on endogenous ERBB2 transcript and protein levels, as well as on transcription promoter activity, by transient-transfection of SKBr3 cells. Reporter gene and chromatin immunoprecipitation assays were used to dissect the ERBB2 promoter and identify functional MBP-1 target sequences. We also investigated the relative expression of MBP-1 and HDAC1 in IDC and normal breast tissues by immunoblot analysis and immunohistochemistry.ResultsTransfection experiments and chromatin immunoprecipitation assays in SKBr3 cells indicated that MBP-1 negatively regulates the ERBB2 gene by binding to a genomic region between nucleotide −514 and −262 of the proximal promoter; consistent with this, a concomitant recruitment of HDAC1 and loss of acetylated histone H4 was observed. In addition, we found high expression of MBP-1 and HDAC1 in normal tissues and a statistically significant inverse correlation with ErbB2 expression in the paired tumor samples.ConclusionsAltogether, our in vitro and in vivo data indicate that the ERBB2 gene is a novel MBP-1 target, and immunohistochemistry analysis of primary tumors suggests that the concomitant high expression of MBP-1 and HDAC1 may be considered a diagnostic marker of cancer progression for breast IDC.

Expression of E-cadherin and β1-integrin mRNA in endometrial cancer

The metastatic ability of tumors is characteristic for malignant neoplasms and constitutes the main cause of therapeutics failures. Metastasis formation involves the sequence of processes such as proteolytic degradation of the basement membrane, migration, intravasation, extravasation, proliferation and angiogenesis. Cadherins and integrins are groups of proteins directly involved in these processes. In the present study we analyzed the mRNA expression of CDH1 and ITGB1 genes by real-time polymerase chain reaction (RT-PCR). The study included 106 endometrial carcinomas. CDH1 and ITGB1 mRNA expression was found in all of the studied samples. Generally the CDH1 and ITGB1 mRNA expression was significantly higher in well-differentiated rather than poorly differentiated tumors. The mRNA expression levels of CDH1 and ITGB1 in series of 83 samples of endometrial carcinoma were studied by real time RT-PCR method. Statistical analysis of the obtained results was performed. CDH1 and ITGB1 gene expression was observed in all examined tissues and was correlated with cancer malignancy (G). In high grade malignant tumors (G1), CDH1 and ITGB1 gene expression was the highest, in G2 and G3 tumors the expression of both genes was gradually lowering. Moreover the statistically significant correlation between CDH1 and ITGB1 gene expression was observed. (Spearman test, r=0.29, p<O.01). CDH1 and ITGB1 mRNA expression seems to be an important marker of cancer progression and metastases in endometrial malignant tumors.

Positive effect of high RKIP expression on reduced distant metastasis by chemotherapy when combined with radiotherapy in locoregionally advanced nasopharyngeal carcinoma: a prospective study

The purpose of this prospective study is to investigate the predictive and prognostic significance of the Raf kinase inhibitory protein (RKIP) in locoregionally advanced nasopharyngeal carcinoma (NPC). Immunohistochemical assays were performed to detect the RKIP protein expression of samples from 212 patients with locoregionally advanced NPC. All patients were assigned randomly into the inductive chemotherapy plus radiation therapy (IC + RT) group, the concurrent chemoradiotherapy (CCRT) group, the inductive chemotherapy plus concurrent chemoradiotherapy (IC + CCRT) group, and the radiation therapy alone (RT) group. The patients in the IC + RT group were treated with IC using 2-3 cycles of cisplatin (80 mg/m(2)) and fluorouracil (500 mg/m(2)), repeated every 3 weeks, followed by radiotherapy. Those in the CCRT group were treated with weekly cisplatin (40 mg/m(2)) for 6-7 cycles during radiotherapy. In the IC + CCRT group, the chemotherapy prior to radiation was similar to the cisplatin-fluorouracil regimen in the IC + RT group, whereas it cisplatin regimen was identical to that in the CCRT group. The results show that RKIP is an independent prognostic factor for 5-year distant metastasis-free survival (DMFS), overall survival (OS), and progression-free survival (PFS). Patients with high RKIP expression benefited more from reduced metastasis in the IC + RT and the IC + CCRT group, with improved OS and PFS in each treatment group compared with that among patients with low RKIP expression. In the high RKIP expression subgroup, chemotherapy combined with radiotherapy improved the DMFS when compared with the RT group, but this effect was not observed in the low RKIP expression subgroup. RKIP was predictive of distant metastasis with good sensitivity and specificity. Clinically, high RKIP expression inhibited distant metastasis in advanced NPC, and its detection might be used to predict distant metastasis with good sensitivity and specificity. The effect of chemotherapy on distant metastasis in combined chemoradiotherapy might be related to the RKIP expression level. Patients with high RKIP expression showed more improved OS and PFS than their low RKIP expression counterparts. Higher RKIP expression improves the DMFS of patients who receive inductive high-dose cisplatin-based chemoradiotherapy, with or without concurrent cisplatin. Low RKIP expression is also a predictive marker for cancer progression and metastasis, which could be used to stratify patients with high risk of metastasis and death.