Prognostic and immunological roles of Fc fragment of IgG binding protein in colorectal cancer

Valuable diagnostic and prognostic biomarkers are urgently needed for colorectal cancer (CRC), which is one of the leading causes of mortality worldwide. Previous studies have reported altered expression of a mucin-like protein Fc fragment of IgG binding protein (FCGBP) in various types of cancer, but its potential diagnostic, prognostic and immunological roles in CRC remain to be determined. Therefore, the aim of current study was to investigate the potential roles of FCGBP in CRC. The present study investigated FCGBP mutations and changes in its expression levels using a combination of microarray and public dataset analyses, as well as immunohistochemistry. The results demonstrated a 10.5% mutation frequency in the FCGBP coding sequence in CRC tissues, and identified decreased FCGBP mRNA or protein expression levels in colorectal adenoma and CRC (compared with those in normal colorectal tissues from healthy control subjects), including pathologically advanced CRC (stage III+IV vs. I+II). Survival analysis using the GEPIA and Kaplan-Meier Plotter databases revealed that low FCGBP expression levels were associated with short overall, disease-free, relapse-free and event-free survival times in patients with CRC. Notably, analysis using the online Tumor IMmune Estimation Resource database revealed a positive correlation between FCGBP expression levels and the extent of infiltrating immune cells, such as B cells and dendritic cells. Consistently, the expression levels of most markers (51/57) for various types of immune cells were significantly correlated with FCGBP expression levels in CRC tissues. These findings suggested that FCGBP may serve as a diagnostic and prognostic biomarker, and that FCGBP may be associated with immune infiltration in CRC.     

Selenium binding protein 1 in ovarian cancer

Selenium binding protein 1 (SELENBP1) was identified to be the most significantly down-regulated protein in ovarian cancer cells by a membrane proteome profiling analysis. SELENBP1 expression levels in 4 normal ovaries, 8 benign ovarian tumors, 12 borderline ovarian tumors and 141 invasive ovarian cancers were analyzed with immunohistochemical assay. SELENBP1 expression was reduced in 87% cases of invasive ovarian cancer (122/141) and was significantly reduced in borderline tumors and invasive cancers (p<0.001). Cox multivariate analysis within the 141 invasive cancer tissues showed that SELENBP1 expression score was a potential prognostic indicator for unfavorable prognosis of ovarian cancer (hazard ratio [HR], 2.18; 95% CI=1.22-3.90; p=0.009). Selenium can disrupt the androgen pathway, which has been implicated in modulating SELENBP1 expression. We investigated the effects of selenium and androgen on normal human ovarian surface epithelial (HOSE) cells and cancer cells. Interestingly, SELENBP1 mRNA and protein levels were reduced by androgen and elevated by selenium treatment in the normal HOSE cells, whereas reversed responses were observed in the ovarian cancer cell lines. These results suggest that changes of SELENBP1 expression in malignant ovarian cancer are an indicator of aberration of selenium/androgen pathways and may reveal prognostic information of ovarian cancer.     

Prognostic biomarkers in resected colorectal cancer: implications for adjuvant chemotherapy

Knowledge of the prognostic role of biomarkers in colorectal cancer is limited and the routine determination for clinical practice is not warranted. However, for some of these markers, data are promising enough for further evaluation. This review addresses a comprehensive analysis of prognostic biomarkers in colorectal cancer. Data from published studies were collected and analyzed. A sufficient level of evidence suggests that DNA indexes, angiogenesis indicators and some genetic/biochemical markers identity prognostic differences in patients with early-stage colorectal cancer. High-risk patients could be the target for future adjuvant chemotherapy trials and one or more of these markers may identify prognostic subgroups with the same TNM stage category.     

Prognostic biomarkers in resected colorectal cancer: implications for adjuvant chemotherapy

Knowledge of the prognostic role of biomarkers in colorectal cancer is limited and the routine determination for clinical practice is not warrented. However, for some of these markers, data are promising enough for further evaluation. This review addresses a comprehensive analysis of prognostic biomarkers in colorectal cancer. Data from published studies were collected and analyzed. A sufficient level of evidence suggests that DNA indexes, angiogenesis indicators and some genetic/biochemical markers identify prognostic differences in patients with early-stage colorectal cancer. High-risk patients could be the target for future adjuvant chemotherapy trials and one or more of these markers may identify prognostic subgroups with the same TNM stage category.     

Exogenous fatty acid binding protein 4 promotes human prostate cancer cell progression

Epidemiologic studies have found that obesity is associated with malignant grade and mortality in prostate cancer. Several adipokines have been implicated as putative mediating factors between obesity and prostate cancer. Fatty acid binding protein 4 (FABP4), a member of the cytoplasmic fatty acid binding protein multigene family, was recently identified as a novel adipokine. Although FABP4 is released from adipocytes and mean circulating concentrations of FABP4 are linked with obesity, effects of exogenous FABP4 on prostate cancer progression are unclear. In this study, we examined the effects of exogenous FABP4 on human prostate cancer cell progression. FABP4 treatment promoted serum‐induced prostate cancer cell invasion in vitro. Furthermore, oleic acid promoted prostate cancer cell invasion only if FABP4 was present in the medium. These promoting effects were reduced by FABP4 inhibitor, which inhibits FABP4 binding to fatty acids. Immunostaining for FABP4 showed that exogenous FABP4 was taken up into DU145 cells in three‐dimensional culture. In mice, treatment with FABP4 inhibitor reduced the subcutaneous growth and lung metastasis of prostate cancer cells. Immunohistochemical analysis showed that the number of apoptotic cells, positive for cleaved caspase‐3 and cleaved PARP, was increased in subcutaneous tumors of FABP4 inhibitor‐treated mice, as compared with control mice. These results suggest that exogenous FABP4 might promote human prostate cancer cell progression by binding with fatty acids. Additionally, exogenous FABP4 activated the PI3K/Akt pathway, independently of binding to fatty acids. Thus, FABP4 might be a key molecule to understand the mechanisms underlying the obesity‐prostate cancer progression link.     

High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses

Recent studies on gene molecular profiling using cDNA microarray in a relatively small series of breast cancer have identified biologically distinct groups with apparent clinical and prognostic relevance. The validation of such new taxonomies should be confirmed on larger series of cases prior to acceptance in clinical practice. The development of tissue microarray (TMA) technology provides methodology for high-throughput concomitant analyses of multiple proteins on large numbers of archival tumour samples. In our study, we have used immunohistochemistry techniques applied to TMA preparations of 1,076 cases of invasive breast cancer to study the combined protein expression profiles of a large panel of well-characterized commercially available biomarkers related to epithelial cell lineage, differentiation, hormone and growth factor receptors and gene products known to be altered in some forms of breast cancer. Using hierarchical clustering methodology, 5 groups with distinct patterns of protein expression were identified. A sixth group of only 4 cases was also identified but deemed too small for further detailed assessment. Further analysis of these clusters was performed using multiple layer perceptron (MLP)-artificial neural network (ANN) with a back propagation algorithm to identify key biomarkers driving the membership of each group. We have identified 2 large groups by their expression of luminal epithelial cell phenotypic characteristics, hormone receptors positivity, absence of basal epithelial phenotype characteristics and lack of c-erbB-2 protein overexpression. Two additional groups were characterized by high c-erbB-2 positivity and negative or weak hormone receptors expression but showed differences in MUC1 and E-cadherin expression. The final group was characterized by strong basal epithelial characteristics, p53 positivity, absent hormone receptors and weak to low luminal epithelial cytokeratin expression. In addition, we have identified significant differences between clusters identified in this series with respect to established prognostic factors including tumour grade, size and histologic tumour type as well as differences in patient outcomes. The different protein expression profiles identified in our study confirm the biologic heterogeneity of breast cancer and demonstrate the clinical relevance of classification in this manner. These observations could form the basis of revision of existing traditional classification systems for breast cancer.     

Predictive and prognostic biomarkers for targeted therapy in metastatic colorectal cancer

The use of targeted biologic agents in combination with chemotherapy has increased the overall survival (OS) of metastatic colorectal cancer (mCRC) to 23.5 months. With the assistance of Kirsten-ras (KRAS) mutational status, the subgroup population resistant to the inhibition of epidermal growth factor receptor (EGFR) by monoclonal antibodies (MoAbs) can be identified. However, only up to a third of the KRAS wild-type subpopulation respond to EGFR inhibition. Multiple factors, including relatively low response rates and high costs for targeted agents, are driving the search to identify further biomarkers within the EGFR/Ras/Raf/Mek/Erk and PTEN/PIP3/AKT signaling pathways. Vascular endothelial growth factor (VEGF) is a key player in tumor angiogenesis and the target for the MoAb bevacizumab, which is currently licensed for use in mCRC. Despite numerous studies, an equivalent predictive biomarker for bevacizumab has not been identified. Preclinical work indicates that inhibition of the insulin growth factor receptor (IGFR) pathway stops cellular transformation and tumor regression, thus identifying this pathway as a strong potential target for anticancer drug development and the identification of novel biomarkers. This review focuses on research relating to the roles of biomarkers within the EGF, VEGF, and IGF receptor pathways. The molecules KRAS, BRAF, NRAS, PTEN, PIP3, VEGF, IGF-1R, and IGF binding protein 3 are discussed. Currently, KRAS is the only biomarker used in clinical practice for mCRC. Pending the results of ongoing and future studies, additional biomarkers will be tested, tailoring our approach to targeted therapy in mCRC.     

Clinical proteomics in breast cancer: a review

Breast cancer imposes a significant healthcare burden on women worldwide. Early detection is of paramount importance in reducing mortality, yet the diagnosis of breast cancer is hampered by the lack of an adequate detection method. In addition, better breast cancer prognostication may improve selection of patients eligible for adjuvant therapy. Hence, new markers for early diagnosis, accurate prognosis and prediction of response to treatment are warranted to improve breast cancer care. Since proteomics can bridge the gap between the genetic alterations underlying cancer and cellular physiology, much is expected from proteome analyses for the detection of better protein biomarkers. Recent technical advances in mass spectrometry, such as matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) and its variant surface-enhanced laser desorption/ionisation (SELDI-) TOF MS, have enabled high-throughput proteome analysis. In the current review, we give a comprehensive overview of the results of expression proteomics (i.e. protein profiling) research performed in breast cancer using these two platforms. Many protein peaks have been reported to bear significant diagnostic, prognostic or predictive value, however, only few candidate markers have been structurally identified yet. In addition, although of pivotal importance in preventing overfitting of data and systematic bias by pre-analytical parameters, validation of biomarker candidates by other, quantitative, methods and/or in new populations is very limited. Moreover, none of the identified candidate biomarkers has been investigated for their utility as breast cancer markers in large, prospective, clinical settings. As such, the candidate biomarkers discussed in this overview have not been validated sufficiently to be used for clinical patient care. Nonetheless, regarding the promising results up to now, MALDI- and SELDI-TOF MS protein profiling studies could eventually fulfil the great promise that protein biomarkers have for improving cancer patient outcome, provided that these studies are performed with adequate statistical power and analytical rigour.     

Progesterone binding cyst protein (PBCP) in primary breast cancer: A new prognostic factor?

Summary Different secretory proteins have been evaluated as possible tumor markers in breast cancer. In this study progesterone binding cyst protein (PBCP) has been quantitated in breast tumor tissue. We report on a correlation of PBCP in cytosols of primary breast cancer, with known prognostic factors. A significant difference (p < 0.001, Chi-square) in the frequency of PBCP-negative patients in clinical Stage I and Stage II is found. This was mainly attributed to a difference between T₁ and T₂ tumors, with less contribution from nodal status. A biological function of PBCP in breast cancer is not known. The distribution of PBCP in our patients has a close resemblance with expected number of node positive patients, suggesting that PBCP as a tumor marker may aid in providing prognostic information in breast cancer patients.     

胃癌RN A结合蛋白相关预后模型的建立和验证

目的:探讨RNA结合蛋白构建的胃癌预后模型并验证其准确性.方法:从癌症基因组图谱(CancerGenome Atlas,TCGA)数据库中下载胃癌的RNA测序数据,并测定正常组织和肿瘤组织中不同表达的RNA结合蛋白(RNA binding protein,RBPs).并系统地研究及分析这些RBPs的表达和预后价值.结果...     

Tumor cell and circulating markers in melanoma: Diagnosis,prognosis, and management

The search is on for biomarkers for use in the diagnosis, staging, prognosis, and management of patients with melanoma. As with many types of cancer, the hematogenous spread of melanoma is a bad prognostic sign, and many groups have attempted to detect circulating melanoma cells in patients with different stages of melanoma. Some studies have used direct extraction of intact tumor cells from the peripheral blood and others the detection of surrogate markers of circulating melanoma cells, such as tyrosinase or MART-1. However, a correlation between the detection of intact melanoma cells in the circulation and prognosis is controversial. Many other biomarkers have also been studied, including lactate dehydrogenase, S100, TA90, and C-reactive protein. Much progress has been made, and preliminary studies have shown promise with many of these markers. Finally, the detection of tumor-specific circulating DNA has shown promise as a prognostic and diagnostic marker of disease in melanoma as well. In this review we examine the most promising biomarkers for use in patients with cutaneous melanoma.     

Inflammatory biomarkers and cancer: CRP and suPAR as markers of incident cancer in patients with serious nonspecific symptoms and signs of cancer

In Denmark, patients with serious nonspecific symptoms and signs of cancer (NSSC) are referred to the diagnostic outpatient clinics (DOCs) where an accelerated cancer diagnostic program is initiated. Various immunological and inflammatory biomarkers have been associated with cancer, including soluble urokinase plasminogen activator receptor (suPAR) and the pattern recognition receptors (PRRs) pentraxin‐3, mannose‐binding lectin, ficolin‐1, ficolin‐2 and ficolin‐3. We aimed to evaluate these biomarkers and compare their diagnostic ability to classical biomarkers for diagnosing cancer in patients with NSSC. Patients were included from the DOC, Department of Infectious Diseases, Copenhagen University Hospital Hvidovre. Patients were given a final diagnosis based on the combined results from scans, blood work and physical examination. Weight loss, Charlson score and previous cancer were registered on admission, and plasma concentrations of biomarkers were measured. The primary outcome was incident cancer within 1 year. Out of 197 patients included, 39 patients (19.8%) were diagnosed with cancer. Patients with cancer were significantly older and had a higher burden of comorbidities and previous cancer diagnoses compared to patients who were not diagnosed with cancer. Previous cancer, C‐reactive protein (CRP) and suPAR were significantly associated with newly diagnosed cancer during follow‐up in multiple logistic regression analyses adjusted for age, sex and CRP. Neither any of the PRRs investigated nor self‐reported weight loss was associated with cancer. In this study, previous cancer, CRP and suPAR were significantly associated with cancer diagnosis in patients with NSSC. Ficolin‐1‐3, MBL and pentraxin‐3 were not associated with cancer.     

Biomarkers in bladder cancer: A metabolomic approach using in vitro and ex vivo model systems

Metabolomics has recently proved to be useful in the area of biomarker discovery for cancers in which early diagnostic and prognostic biomarkers are urgently needed, as is the case of bladder cancer (BC). This article presents a comprehensive review of the literature on the metabolomic studies on BC, highlighting metabolic pathways perturbed in this disease and the altered metabolites as potential biomarkers for BC detection. Current disease model systems used in the study of BC metabolome include in vitro‐cultured cancer cells, ex vivo neoplastic bladder tissues and biological fluids, mainly urine but also blood serum/plasma, from BC patients. The major advantages and drawbacks of each model system are discussed. Based on available data, it seems that BC metabolic signature is mainly characterized by alterations in metabolites related to energy metabolic pathways, particularly glycolysis, amino acid and fatty acid metabolism, known to be crucial for cell proliferation, as well as glutathione metabolism, known to be determinant in maintaining cellular redox balance. In addition, purine and pyrimidine metabolism as well as carnitine species were found to be altered in BC. Finally, it is emphasized that, despite the progress made in respect to novel biomarkers for BC diagnosis, there are still some challenges and limitations that should be addressed in future metabolomic studies to ensure their translatability to clinical practice.     

Clinical development of mTOR inhibitors in breast cancer

The mammalian target of rapamycin (mTOR) pathway is a central pathway that regulates mRNA translation, protein synthesis, glucose metabolism, lipid synthesis and autophagy, and is involved in malignant transformation. Several randomized trials have shown that the use of mTOR inhibitors could improve patient outcome with hormone receptor-positive or human epidermal growth factor receptor-2-positive breast cancer. This review analyzes new perspectives from these trials. Preclinical studies have suggested that the mTOR pathway may play a role in the resistance to hormone therapy, trastuzumab and chemotherapy for breast cancer. This concept has been tested in clinical trials for neoadjuvant treatment and for metastatic breast cancer patients. Also, much effort has gone into the identification of biomarkers that will allow for more precise stratification of patients. Findings from these studies will provide indispensable tools for the design of future clinical trials and identify new perspectives and challenges for researchers and clinicians.     

Functional Magnetic Resonance Imaging in Cervical Cancer Diagnosis and Treatment

Cervical Cancer is the fourth most common cancer in women worldwide. Treatment with chemoradiotherapy followed by brachytherapy achieves high local control, but recurrence with metastatic disease impacts survival. This highlights the need for predictive and prognostic biomarkers identifying populations at risk of poorer treatment response and survival. Magnetic resonance imaging (MRI) is routinely used in cervical cancer and is a potential source for biomarkers. Functional MRI (fMRI) can characterise tumour beyond anatomical MRI, which is limited to the assessment of morphology. This review summarises fMRI techniques used in cervical cancer and examines the role of fMRI parameters as predictive or prognostic biomarkers. Different techniques characterise different tumour factors, which helps to explain the variation in patient outcomes. These can impact simultaneously on outcomes, making biomarker identification challenging. Most studies are small, focussing on single MRI techniques, which raises the need to investigate combined fMRI approaches for a more holistic characterisation of tumour.     

Early diagnostic protein biomarkers for breast cancer: how far have we come?

Many studies have used surface-enhanced laser desorption/ionization time-of-flight mass spectrometry or matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to search for blood-based proteins that are related to the presence of breast cancer. We review the biomarkers discovered or targeted measured by these methods and discuss the strengths and weaknesses of these studies. We highlight two proteins that were most often related to breast cancer: C3a des-arginine anaphylatoxin (C3adesArg) (molecular weight: 8,938 Da) and fragments of inter-alpha trypsin inhibitor heavy chain H4 (ITIH4). In addition, we elaborate on three important methodological aspects related to these studies: protein identification, specificity of the markers, and disease heterogeneity. Finally, we propose some points to be addressed in future studies. These include the use of other analytical measurement techniques, need of protein identification, the importance of identical sample handling protocols for cases and controls, and the stratification of the results according to molecular subtypes and stages of breast cancer. Ultimately this may lead to the discovery of new and valid breast cancer specific biomarkers.     

Role of miRNA in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. Evidence suggests that miRNAs play an important role in progression, recurrence, metastasis and postoperative survival of HNSCC. Studies have investigated the utility of miRNAs as diagnostic/prognostic tools and as potential therapeutic targets and biomarkers that may improve the management and outcomes of HNSCC. The aim of this article is to review the current literature on aberrant expression profiles of miRNAs in biopsy samples of HNSCC and their role in cancer development, metastasis, prognosis and survival of these patients. This review gives an overview that miRNAs deregulation play major role in the development of HNSCC. They offer the potential to be used as biomarkers or novel therapeutic targets. Future research is required to test their use in both of these fields.     

Periostin: A Novel Prognostic and Therapeutic Target For Genitourinary Cancer?

Many of the cellular abnormalities present in solid tumors are structural in nature and involve the proteins of the extracellular matrix (ECM). Periostin is a protein produced and secreted by the fibroblasts as a component of the ECM where it is involved in regulating intercellular adhesion. The expression of periostin has an important physiological role during embryogenesis and growth, namely at the level of bone, dental, and cardiac tissues. Many studies indicate that periostin plays an important role for tumor progression in various types of cancer, such as colon, lung, head and neck, breast, ovarian, and prostate. To the best of our knowledge, a limited number of studies have investigated periostin expression in urogenital cancer, such as prostate, bladder, penile, and renal cancer, and no studies were performed in testis cancer. In this review article, we summarize the most recent knowledge of periostin, its genetic and protein structure, and the role of the different isoforms identified and sequenced so far. In particular, we focus our attention on the role of this protein in genitourinary tumors, trying to emphasize the role not only as a possible prognostic marker, but also as a possible target for the development of future anticancer therapies.