Biomarkers discovery in cancer--up-dates in methodology

Biomarkers are biomolecules that can indicate normal/pathological processes, or physiological responses to therapy. Due to the serum abundance in proteins, such as albumin and lypo/glycoproteins, biomarkers are difficult to assess. Serum biomarkers identification can contribute to personalized medicine and improve cancer diagnostic and prognostic. The paper summarizes some of the proteomics techniques and the workflow used for protein signatures identification associated to cancer development. Thus, biomarkers validated for prostatic, breast, cervical or lung cancers are presented as examples for clinical application of serum markers. In spite of the continuous research efforts, there are only few validated biomarkers that have proved a good predictive power in cancer. Modern technology and the combination of various techniques used for proteins quantification represent important means for the identification and validation of new biomarkers.     

Circulating microRNAs as potential diagnostic biomarkers and therapeutic targets in prostate cancer: Current status and future perspectives

Prostate cancer (PCa) is one of the most common malignancies among men. Despite advancement in technology and medicine over past decades, late diagnosis remains a critical milestone in effective treatment. Therefore, it is necessary to identify novel and reliable biomarkers which are specifically sensitive and specific for prognosis and prediction of clinical outcomes. MicroRNAs (miRNAs) play important roles in posttranslational regulations of genes. Circulating and exosomal miRNAs can be applied as useful diagnostic markers for a different type of malignancies, including PCa. Herein, we summarized various roles of miRNAs (diagnostic, therapeutic, and prognostic) in PCa. Moreover, we highlighted exosomal miRNAs as a new candidate in diagnosis and monitoring response to therapy in patients with PCa.     

Melanoma: Where we are and where we go

Melanoma is known as an aggressive tumor which shows an increasing incidence and poor prognosis in the metastatic phase. Hence, it seems that diagnosis and effective management (including early diagnosis, choosing of the effective therapeutic platform, caring, and training of patients for early detection) are major aspects of melanoma therapy. Early detection of melanoma is a key point for melanoma therapy. There are various diagnosis options such as assessing of biopsy, imaging techniques, and biomarkers (i.e., several proteins, polymorphism, and liquid biopsy). Among the various biomarkers, assessing circulating tumor cells, cell-free DNAs, cell-free RNAs, and microRNAs (miRNAs) have emerged as powerful diagnosis tools for melanoma patients. Deregulations of these molecules are associated with melanoma pathogenesis. After detection of melanoma, choosing of effective therapeutic regimen is a key step for recovery of melanoma patients. Several studies indicated that various therapeutic approaches including surgery, immunotherapy, systematic therapy, radiation therapy and antibodies therapy could be used as potential therapeutic candidates for melanoma therapy. Caring for melanoma patients is one of the important components of melanoma therapy. Caring and training for melanoma patients could contribute to better monitoring of patients in response to various therapeutic options. Here, we summarized various diagnosis approaches such as assessing biopsy, imaging techniques, and utilization of various biomarkers (i.e., proteins, CTCs, cfDNAs, and miRNAs) as a diagnostic biomarker for detection and monitoring patients with melanoma. Moreover, we highlighted various therapeutic options and caring aspects in patients with melanoma.     

MicroRNAs as potential investigative and predictive biomarkers in colorectal cancer

Colorectal cancer (CRC) is a noticeable reason of cancer-associated deaths with a high incidence and mortality rate. Countless effort have been put into the improving clinical management of CRC patients including more effective tools and a wide variety of biomarkers for diagnostic, prognostic or predictive purposes. In recent years, dysregulated miRNAs have been emerged as highly sensitive and specific markers to manage CRC in an effective way. They can play key roles in carcinogenesis as potential oncogenes, tumor suppressors or regulators of cancer network. Therefore, miRNAs may serve as molecular tools that can be quantified and used in diagnostic and prognostic approaches. Growing evidence also suggests that forced expression of tumor suppressor miRNAs or inhibiting the oncogene ones, can be used as a novel treatment strategy. In this review, we focus on the clinical applications of miRNAs as promising biomarkers of early cancer detection, prognosis and treatment.     

Markers of small cell lung cancer

Lung cancer is the number one cause of cancer death; however, no specific serum biomarker is available till date for detection of early lung cancer. Despite good initial response to chemotherapy, small-cell lung cancer (SCLC) has a poor prognosis. Therefore, it is important to identify molecular markers that might influence survival and may serve as potential therapeutic targets. The review aims to summarize the current knowledge of serum biomarkers in SCLC to improve diagnostic efficiency in the detection of tumor progression in lung cancer. The current knowledge on the known serum cytokines and tumor biomarkers of SCLC is emphasized. Recent findings in the search for novel diagnostic and therapeutic molecular markers using the emerging genomic technology for detecting lung cancer are also described. It is believed that implementing these new research techniques will facilitate and improve early detection, prognostication and better treatment of SCLC.     

Proteomic analysis of cancer tissues: shedding light on carcinogenesis and possible biomarkers

Lung, gastric, colorectal, pancreatic, and esophageal cancers, as well as hepatocellular carcinoma (HCC), were the six most common and highly fatal cancers for Japanese men in Japan in 2003, while for women uterine cervical cancer could also be added to this list. To identify diagnostic or therapeutic biomarkers for these cancers, investigators are nowadays performing proteomic analyses of cancer tissues and cells, and revealing a large number of molecules which are diagnostic, prognostic and informative of carcinogenesis. From reports of proteomic analyses of cancerous tissues and noncancerous tissues sampled from HCC, and pancreatic, esophageal, gastric, colorectal, lung and uterine cervical cancers, we classified the proteins into digestive enzymes, growth factors, cell adhesion molecules, calcium-binding proteins, proteases, protease inhibitors, transporter proteins, structural molecules, apoptosis inhibitor, molecular chaperone, as well as proteins related to cell growth, cell differentiation, cell transformation, tumor invasion, carcinogen metabolism, and others. The aim of this study was to understand carcinogenesis of major cancers from a proteomics perspective using samples from cancer patients, and to elucidate their tumor biomarkers.     

Proteomic analysis at the bedside: early detection of cancer

Proteomic technologies promise to accelerate rapidly a new era in molecular medicine, especially in the detection and discovery of disease-related biomarkers. These technologies have no bigger impact than in the field of human cancer research. Beyond lifestyle-associated prevention strategies, early detection of cancer has the most profound impact on the ultimate course of the disease: the earlier the cancer is detected, the better the prognosis. Today, new proteomic technologies are being used to discover new diagnostic and prognostic biomarkers for the early detection and treatment of cancer that will have important implications at the bedside.     

LncRNAs as potential diagnostic and prognostic biomarkers in gastric cancer: A novel approach to personalized medicine

Gastric cancer is the third leading cause of cancer death with 5-year survival rate of about 30–35%. Since early detection is associated with decreased mortality, identification of novel biomarkers for early diagnosis and proper management of patients with the best response to therapy is urgently needed. Long noncoding RNAs (lncRNAs) due to their high specificity, easy accessibility in a noninvasive manner, as well as their aberrant expression under different pathological and physiological conditions, have received a great attention as potential diagnostic, prognostic, or predictive biomarkers. They may also serve as targets for treating gastric cancer. In this review, we highlighted the role of lncRNAs as tumor suppressors or oncogenes that make them potential biomarkers for the diagnosis and prognosis of gastric cancer. Relatively, lncRNAs such as H19, HOTAIR, UCA1, PVT1, tissue differentiation-inducing nonprotein coding, and LINC00152 could be potential diagnostic and prognostic markers in patients with gastric cancer. Also, the impact of lncRNAs such as ecCEBPA, MLK7-AS1, TUG1, HOXA11-AS, GAPLINC, LEIGC, multidrug resistance-related and upregulated lncRNA, PVT1 on gastric cancer epigenetic and drug resistance as well as their potential as therapeutic targets for personalized medicine was discussed.     

Exosomes and microRNAs: New potential therapeutic candidates in Alzheimer disease therapy

Exosomes are biological nanocarriers which could be involved in a variety of basic physiological events. They exert their effects via targeting their cargos (i.e., DNAs, messenger RNAs, microRNAs [miRNAs], and proteins) to host cells, which led to change behaviors of recipient cells. One of the important aspects of exosomes is the roles of them in disease conditions. Increasing evidence indicated that exosomes are one of the main players in Alzheimer’s disease (AD) pathogenesis. Hence, it seems that these nanocarriers could be used as diagnostic and therapeutic biomarkers in AD treatment. Another important player in AD pathogenesis is miRNA. MiRNAs are short noncoding RNAs which exert their effects as epigenetic regulators. These molecules involved in different stages of AD. Therefore, miRNAs could be used as prognostic, diagnostic, and therapeutic biomarkers in AD. Here, we summarized various roles of exosomes and application of them in AD pathogenesis. Moreover, we highlighted the utilization of miRNAs as a therapeutic option in AD therapy.     

Detecting microRNAs of high influence on protein functional interaction networks: a prostate cancer case study

ABSTRACT: BACKGROUND: The use of biological molecular network information for diagnostic and prognostic purposes and elucidation of molecular disease mechanism is a key objective in systems biomedicine. The network of regulatory miRNA-target and functional protein interactions is a rich source of information to elucidate the function and the prognostic value of miRNAs in cancer. The objective of this study is to identify miRNAs that have high influence on target protein complexes in prostate cancer as a case study. This could provide biomarkers or therapeutic targets relevant for prostate cancer treatment. RESULTS: Our findings demonstrate that a miRNA's functional role can be explained by its target protein connectivity within a physical and functional interaction network. To detect miRNAs with high influence on target protein modules, we integrated miRNA and mRNA expression profiles with a sequence based miRNA-target network and human functional and physical protein interactions (FPI). miRNAs with high influence on target protein complexes play a role in prostate cancer progression and are promising diagnostic or prognostic biomarkers. We uncovered several miRNA-regulated protein modules which were enriched in focal adhesion and prostate cancer genes. Several miRNAs such as miR-96, miR-182, and miR-143 demonstrated high influence on their target protein complexes and could explain most of the gene expression changes in our analyzed prostate cancer data set. CONCLUSIONS: We describe a novel method to identify active miRNA-target modules relevant to prostate cancer progression and outcome. miRNAs with high influence on protein networks are valuable biomarkers that can be used in clinical investigations for prostate cancer treatment.     

Serum-based protein biomarkers for detection of lung cancer

Lung cancer is one of the most common cancers in terms of both incidence and mortality.The major reasons for the increasing number of deaths from lung cancer are late detection and lack of effective therapies. To improve our understanding of lung cancer biology, there is urgent need for blood-based, non-invasive molecular tests to assist in its detection in a cost-effective manner at an early stage when curative interventions are still possible. Recent advances in proteomic technology have provided extensive, high throughput analytical tools for identification, characterization and functional studies of proteomes. Changes in protein expression patterns in response to stimuli can serve as indicators or biomarkers of biological and pathological processes as well as physiological and pharmacological responses to drug treatment, thus aiding in early diagnosis and prognosis of disease. However, only a few biomarkers have been approved by the FDA to date for screening and diagnostic purposes. This review provides a brief overview of currently available proteomic techniques, their applications and limitations and the current state of knowledge about important serum biomarkers in lung cancer and their potential value as prognostic and diagnostic tools.     

An overview of prostate cancer (PCa) diagnosis: Potential role of miRNAs

Prostate cancer is the second most frequently diagnosed cancer among men worldwide, with the estimated sixth leading cause of cancer death. Despite major advancements in clinical biology and imaging, digital rectal examination (DRE), prostate-specific antigen (PSA), and biopsies indication remain the keystone for screening. Several kits are used to detect genomic changes and non-coding RNAs in the sample. However, its indication remains controversial for screening purposes. There is an urged need for non-invasive biomarkers to implement precision medicine. Recent research shows that miRNAs have an important role in the diagnostic, prognostic, and therapeutic agents as non-invasive biomarkers. Though prostate cancer data remains controversial in other cancer types, such as breast cancer, miR-21 expression is upregulated. Here, we reported a prolonged revision of miRNAs as prostate cancer prognostic, diagnostic, and predictive tools, including data on androgen receptor (AR) signaling, epithelial-mesenchymal transition (EMT) process, and cancer stem cells (CSCs) regulation. The combined utilization of miRNAs with other tests will help patients and clinicians to select the most appropriate personalized treatment and to avoid overdiagnosis and unnecessary biopsies. Future clinical applications of our reported novel miRNAs have a substantial role in the primary diagnosis of prostate cancer to help treatment decisions.     

Oncometabolomics in cancer research

Cancer is not only a complex genetic disease, but also a disease of dysregulated bioenergetic metabolism. With improved technological advancements, the focus has shifted from changes in an individual biochemical pathway or metabolite toward changes in the context of the global network of metabolic pathways in a cell, tissue or organism. This global approach allows identifying changes in the pattern of metabolite expression in addition to changes in individual metabolite or pathway. Such a metabolomics approach promises a better understanding of tumor biology and identification of potential biomarkers with applications as diagnostic, prognostic and therapeutic targets. In this review, we discuss various techniques used in metabolomics and analysis of the data generated and its specific uses in cancer research including novel biomarker identification, development of more sensitive and specific diagnostic methods, monitoring of currently used cancer therapeutics to evaluate the prognostic outcome with a given therapy and evaluating novel therapeutic strategies.     

Protein arrays as tools for serum autoantibody marker discovery in cancer

Protein array technology has begun to play a significant role in the study of protein–protein interactions and in the identification of antigenic targets of serum autoantibodies in a variety of autoimmune disorders. More recently, this technology has been applied to the identification of autoantibody signatures in cancer.The identification of tumour-associated antigens (TAAs) recognised by the patient's immune response represents an exciting approach to identify novel diagnostic cancer biomarkers and may contribute towards a better understanding of the molecular mechanisms involved. Circulating autoantibodies have not only been used to identify TAAs as diagnostic/prognostic markers and potential therapeutic targets, they also represent excellent biomarkers for the early detection of tumours and potential markers for monitoring the efficacy of treatment. Protein array technology offers the ability to screen the humoral immune response in cancer against thousands of proteins in a high throughput technique, thus readily identifying new panels of TAAs. Such an approach should not only aid in improved diagnostics, but has already contributed to the identification of complex autoantibody signatures that may represent disease subgroups, early diagnostics and facilitated the analysis of vaccine trials.     

Combined analysis of HPV DNA and p16INK4a expression to predict prognosis in ASCUS and LSIL pap smears

Human papillomavirus (HPV) is known to play an important etiological role in the genesis of cervical cancer, but only a very small proportion of infected women develop invasive cervical cancer. The purpose of cervical cancer prevention is early diagnosis of its precursors. The molecular detection of HPV DNA as a diagnostic test to cervical carcinogenesis gave a low positive predictive value as compared to the use of biomarkers. p16INK4a has been proposed as putative surrogate biomarkers that would allow identification of dysplastic cervical epithelia. Serial consecutive cervical smears were test for high-risk HPV stained with immunocytochemistry for p16INK4a and followed-up for 36 months. The aim of the study was to evaluate the immunohistochemical expression of pl6INK4a as a marker of progression risk in low-grade dysplastic lesions of the cervix uteri. In the present series, significant pl6 overexpression was observed in the group that progressed from low to high-grade squamous intraepithelial lesion when compared with the group that did not progress. In conclusion, overexpression of p16INK4a acts as potential biomarkers for cervical cancer progression from premalignant lesions.     

Genomic and proteomic biomarkers for cancer: A multitude of opportunities

Biomarkers are molecular indicators of a biological status, and as biochemical species can be assayed to evaluate the presence of cancer and therapeutic interventions. Through a variety of mechanisms cancer cells provide the biomarker material for their own detection. Biomarkers may be detectable in the blood, other body fluids, or tissues. The expectation is that the level of an informative biomarker is related to the specific type of disease present in the body. Biomarkers have potential both as diagnostic indicators and monitors of the effectiveness of clinical interventions. Biomarkers are also able to stratify cancer patients to the most appropriate treatment. Effective biomarkers for the early detection of cancer should provide a patient with a better outcome which in turn will translate into more efficient delivery of healthcare. Technologies for the early detection of cancer have resulted in reductions in disease-associated mortalities from cancers that are otherwise deadly if allowed to progress. Such screening technologies have proven that early detection will decrease the morbidity and mortality from cancer. An emerging theme in biomarker research is the expectation that panels of biomarker analytes rather than single markers will be needed to have sufficient sensitivity and specificity for the presymptomatic detection of cancer. Biomarkers may provide prognostic information of disease enabling interventions using targeted therapeutic agents as well as course-corrections in cancer treatment. Novel genomic, proteomic and metabolomic technologies are being used to discover and validate tumor biomarkers individually and in panels.     

Cancer Liquid Biopsy Using Integrated Microfluidic Exosome Analysis Platforms

Liquid biopsies serve as both powerful noninvasive diagnostic tools for early cancer screening and prognostic tools for monitoring cancer progression and treatment efficacy. Exosomes are promising biomarkers for liquid biopsies, since these nano‐sized extracellular vesicles (EVs) enrich proteins, lipids, mRNAs, and miRNAs from cells of origin, including cancer cells. Although exosomes are abundantly present in various bodily fluids, conventional exosome isolation and detection methods that rely on benchtop equipment are time‐consuming, expensive, and involve complicated non‐portable procedures. As an alternative, recently developed microfluidic platforms can perform effective exosome separation and detection for liquid biopsies using a single device. Such methods offer advantages of integrity, speed, cost‐efficiency, and portability over conventional benchtop and early microfluidic‐based single‐functional methods which can only separate or detect exosomes separately. These advances have made exosome‐based point‐of‐care (POC) applications possible. This review outlines recent integrated microfluidic‐based exosomal detection strategies to guide future development of such devices for use in liquid biopsies for early cancer screening, prognostic monitoring, and other potential POC applications.     

用于肿瘤治疗的免疫检查点抑制剂相关预测生物标志物的研究进展

恶性肿瘤是严重威胁人类健康和社会发展的疾病。传统的肿瘤治疗方法如手术、放疗、化疗和靶向治疗等不能完全满足临床治疗的需求,新兴的免疫治疗成为了肿瘤治疗领域的研究热点。免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)作为一种肿瘤免疫治疗方法,已获批用于治疗多种肿瘤,如肺癌、肝癌、胃癌和结直肠癌等。然而,ICIs在临床使用过程中,只有少数患者会出现持久反应,一些患者还会出现耐药和不良反应。因此,预测生物标志物的鉴定和开发对提高ICIs的治疗效果至关重要。肿瘤ICIs预测生物标志物主要包括肿瘤生物标志物、肿瘤微环境生物标志物、循环相关生物标志物、宿主环境生物标志物以及组合生物标志物等,对患者筛查、个体化治疗和预后评估具有重要意义。本文就肿瘤ICIs治疗预测生物标志物的前沿进展作一综述。