The cancer secretome,current status and opportunities in the lung,breast and colorectal cancer context

Despite major improvements on the knowledge and clinical management, cancer is still a deadly disease. Novel biomarkers for better cancer detection, diagnosis and treatment prediction are urgently needed. Proteins secreted, shed or leaking from the cancer cell, collectively termed the cancer secretome, are promising biomarkers since they might be detectable in blood or other biofluids. Furthermore, the cancer secretome in part represents the tumor microenvironment that plays a key role in tumor promoting processes such as angiogenesis and invasion. The cancer secretome, sampled as conditioned medium from cell lines, tumor/tissue interstitial fluid or tumor proximal body fluids, can be studied comprehensively by nanoLC-MS/MS-based approaches. Here, we outline the importance of current cancer secretome research and describe the mass spectrometry-based analysis of the secretome. Further, we provide an overview of cancer secretome research with a focus on the three most common cancer types: lung, breast and colorectal cancer. We conclude that the cancer secretome research field is a young, but rapidly evolving research field. Up to now, the focus has mainly been on the discovery of novel promising secreted cancer biomarker proteins. An interesting finding that merits attention is that in cancer unconventional secretion, e.g. via vesicles, seems increased. Refinement of current approaches and methods and progress in clinical validation of the current findings are vital in order to move towards applications in cancer management. This article is part of a Special Issue entitled: An Updated Secretome.     

The cancer cell secretome: A good source for discovering biomarkers?

Cancer is a leading cause of death. Early detection is usually associated with better clinical outcomes. Recent advances in genomics and proteomics raised hopes that new biomarkers for diagnosis, prognosis or monitoring therapeutic response will soon be discovered. Proteins secreted by cancer cells, referred also as “the cancer cell secretome”, is a promising source for biomarker discovery. In this review we will summarize recent advances in cancer cell secretome analysis, focusing on the five most fatal cancers (lung, breast, prostate, colorectal, and pancreatic). For each cancer type we will describe the proteomic approaches utilized for the identification of novel biomarkers. Despite progress, identification of markers that are superior to those currently used has proven to be a difficult task and very few, if any, newly discovered biomarker has entered the clinic the last 10 years.     

Crucial considerations for pipelines to validate circulating biomarkers for breast cancer

Despite decades of progress in breast imaging, breast cancer remains the second most common cause of cancer mortality in women. The rapidly proliferative breast cancers that are associated with high relapse rates and mortality frequently present in younger women, in unscreened individuals, or in the intervals between screening mammography. Biomarkers exist for monitoring metastatic disease, such as CEA, CA27.29 and CA15-3, but there are no circulating biomarkers clinically available for early detection, prognosis, or monitoring for clinical relapse. There has been significant progress in the discovery of potential circulating biomarkers, including proteins, autoantibodies, nucleic acids, exosomes, and circulating tumor cells, but the vast majority of these biomarkers have not progressed beyond initial research discovery, and none have yet been approved for clinical use in early stage disease. Here, the authors review the crucial considerations of developing pipelines for the rapid evaluation of circulating biomarkers for breast cancer.     

Classification moléculaire des cancers du sein : utilité en clinique

In spite of the progress of treatments and the discovery of targeted therapies, breast cancer remains the leading cause of cancer mortality among women. It is also the first cancer to get benefits from target therapies against hormone receptors and now HER2. The anatomoclinical classification used to optimize the therapeutics is not always accurate and is a cause of overtreatments or of inappropriate treatments. Tumour cells genomic studies have shown the relationship between genomic alterations and the prognosis and the efficacy of treatments. The molecular classification which results from those studies allowed the emergence of numerous diagnostic tests. They use different technologies and different clinical approaches which should allow a better classification in order to be able to propose a personalized therapy. In this review, eight molecular tests are estimated compared to their scientific validation and to their clinical utility. Protein assays are also reviewed as uPA/PAI-1, the only prognostic marker validated with a level of evidence 1.     

Somatic oncogenic mutations,benign skin lesions and cancer progression: Where to look next?

Somatic oncogenic activating mutations in FGFR3 and/or PIK3CA have recently been described in benign epithelial cutaneous lesions that never progress to malignancy (seborrheic keratoses and epidermal nevi). The same mutations have been observed in malignant neoplasms from other tissues (bladder carcinoma, cervix cancer, colorectal cancer, myeloma). However, many of the above-mentioned epithelial benign cutaneous tumors do not harbour mutations in FGFR3 or PIK3CA. In this review, we focus on new candidate genes for discovery and we outline the potential of the skin as a model to achieve a better understanding of cancer biology.     

Discovery and Validation of Clinical Biomarkers of Cancer: A Review Combining Metabolomics and Proteomics

Early detection and diagnosis of cancer can allow timely medical intervention, which greatly improves chances of survival and enhances quality of life. Biomarkers play an important role in assisting clinicians and health care providers in cancer diagnosis and treatment follow‐up. In spite of years of research and the discovery of thousands of candidate cancer biomarkers, only a few have transitioned to routine usage in the clinic. This review highlights advances in proteomics technologies that have enabled high rates of discovery of candidate cancer biomarkers and evaluates integration with other omics technologies to improve their progress through to validation and clinical translation. Furthermore, it gauges the role of metabolomics technology in cancer biomarker research and assesses it as a complementary tool in aiding cancer biomarker discovery and validation.     

美国国家癌症研究所(National Cancer Institute)--美国癌症研究和资助的主要机构

美国国家癌症研究所(National Cancer Institute,NCI)成立于1937年,是国立卫生研究院(National Institutes of Health,NIH)历史最为悠久的研究所,也是美国癌症研究和资助的主要机构。通过立法及增加对癌症研究的投入,NCI在癌症研究领域取得一些成绩,使肺癌、结直肠癌、乳腺癌及前列腺癌的死亡率持续下降,另在胰腺癌、卵巢癌、白血病和甲状腺癌等肿瘤的诊断和治疗方面也取得了巨大成就。新近NCI制定了到20l5年的奋斗目标：“消除痛苦、减少死亡”,并将主要策略由“寻找进而破坏(seekanddestory)”转为“锁定并且控制(target and control)”。为了实现上述目标,NCI提出必须加强基础研究,以利癌症的早期发现(discovery);以此为基础,将实验室的研究结果尽快用于临床,促进各种治疗措施的发展(development);加强癌症防治的公共卫生宣传,以利于健康资讯的发布(delivery)。本文将简述NCI的历史沿革、主要目标、组织结构、资金预算以及所取得的成就。     

Dampening Enthusiasm for Circulating MicroRNA in Breast Cancer

Genome-wide platforms for high-throughput profiling of circulating miRNA (oligoarray or miR-Seq) offer enormous promise for agnostic discovery of circulating miRNA biomarkers as a pathway for development in breast cancer detection. By harmonizing data from 15 previous reports, we found widespread inconsistencies across prior studies. Whether this arises from differences in study design, such as sample source or profiling platform, is unclear. As a reproducibility experiment, we generated a genome-wide plasma miRNA dataset using the Illumina oligoarray and compared this to a publically available dataset generated using an identical sample size, substrate and profiling platform. Samples from 20 breast cancer patients, 20 mammography-screened controls, as well as 20 breast cancer patients after surgical resection and 10 female lung or colorectal cancer patients were included. After filtering for miRNAs derived from blood cells, and for low abundance miRNAs (non-detectable in over 10% of samples), a set of 522 plasma miRNAs remained, of which 46 were found to be differentially expressed between breast cancer patients and healthy controls (p<0.05), of which only 3 normalized to baseline levels in post-resection cases and were unique to breast cancer vs. lung or colorectal cancer (miR-708*, miR-92b* and miR-568, none previously reported). We were unable to demonstrate reproducibility by various measures between the two datasets. This finding, along with widespread inconsistencies across prior studies, highlight the need for better understanding of factors influencing circulating miRNA levels as prerequisites to progress in this area of translational research.     

Proteomics and its applications for biomarker discovery in human saliva

Human saliva is a biological fluid with enormous diagnostic potential. Because saliva can be non-invasively collected, it provides an attractive alternative for blood, serum or plasma. It has been postulated that the blood concentrations of many components are reflected in saliva. Saliva harbors a wide array of proteins, which can be informative for the detection of diseases. Profiling the proteins in saliva over the course of disease progression could reveal potential biomarkers indicative of different stages of diseases, which may be useful in medical diagnostics. With advanced instrumentation and developed refined analytical techniques, proteomics is widely envisioned as a useful and powerful approach for salivary proteomic biomarker discovery. As proteomic technologies continue to mature, salivary proteomics have great potential for biomarker research and clinical applications. The progress and current status of salivary proteomics and its application in the biomarker discovery of oral and systematic diseases will be reviewed. The scientific and clinical challenges underlying this approach will also be discussed.     

放射性药物在肿瘤靶向治疗中的应用

放射性药物指供临床诊断或治疗用的放射性核素制剂或其标记化合物。放射性核素靶向治疗是利用对肿瘤细胞具有特异高亲和力的分子载体将核素定向导入特定的肿瘤组织,对肿瘤进行治疗。与传统的放疗和化疗相比,其具有选择性杀伤肿瘤细胞的特点。随着核医学的发展,SPECT/CT、PET/CT的普及,新靶点的发现和新型放射性药物的研发,利用放射性药物进行靶向治疗在肿瘤临床治疗中占据的地位越来越重要。本文简述了放射性药物的分类、组成及特点;综述了针对肿瘤相关抗原的放射免疫药物在非霍奇金淋巴瘤、结直肠癌和前列腺癌中的应用;受体介导的放射性核素药物在治疗神经内分泌肿瘤、前列腺癌和乳腺癌中的临床应用以及基于基因修饰的放射性药物在肿瘤靶向治疗中的实验研究进展。最后总结了放射性药物在肿瘤靶向治疗中的应用前景与面临的挑战,以期为靶向治疗肿瘤的放射性药物的开发和临床应用提供一些参考。     

Molecular pathology of colorectal cancer.

The identification of several types of familial colorectal cancer has led to the discovery of some of the genes involved in these diseases. It was subsequently shown that somatic mutations of these genes (APC, mismatch repair genes, TP53, KRAS, and DCC) also occur in sporadic colorectal cancer. Gradually, this molecular information is being incorporated into the standard histopathological analysis of colorectal cancer and can be used for the characterization of primary tumors. Although attempts have been made to use molecular parameters to better define dysplasia grades, differentiate between adenoma and carcinoma, and subtype carcinomas, histological parameters remain the standard for the classification of primary tumors. Nonetheless, molecular parameters may help define subgroups of colorectal carcinoma differing in prognosis and requiring individualized treatment regimens. Interesting possibilities are predicting the response to chemotherapy or radiotherapy at a molecular level and the search for metastasis by looking for molecular markers in lymph nodes or circulating blood. Other pathological tests being developed include the detection of KRAS, TP53, or APC mutations in stool and plasma. Such approaches will have a significant impact on the clinical management of colorectal cancer.     

Proteomics and its applications for biomarker discovery in human saliva

Human saliva is a biological fluid with enormous diagnostic potential. Because saliva can be non-invasively collected, it provides an attractive alternative for blood, serum or plasma. It has been postulated that the blood concentrations of many components are reflected in saliva. Saliva harbors a wide array of proteins, which can be informative for the detection of diseases. Profiling the proteins in saliva over the course of disease progression could reveal potential biomarkers indicative of different stages of diseases, which may be useful in medical diagnostics. With advanced instrumentation and developed refined analytical techniques, proteomics is widely envisioned as a useful and powerful approach for salivary proteomic biomarker discovery. As proteomic technologies continue to mature, salivary proteomics have great potential for biomarker research and clinical applications. The progress and current status of salivary proteomics and its application in the biomarker discovery of oral and systematic diseases will be reviewed. The scientific and clinical challenges underlying this approach will also be discussed.     

Targeting autophagy

In recent years, tremendous progress has been made toward unveiling the mechanism of autophagy and its exploitation by many different cancer types. This year the American Association for the Advancement of Science held a one day Symposium on Autophagy: An Emerging Therapeutic Target in Human Disease in Vancouver, British Columbia and brought together experts in cell biology, drug discovery, and clinical translation to share their research findings and prospects. Currently, autophagy is being investigated on several fronts, from modulation of gene expression to in vivo studies, and more recently clinical trials in cancer. Key topics of discussion were determining which stage of autophagy would be the ideal target for inhibition to produce the highest impact, and which cancers or cancer subtypes would be the most sensitive to autophagy inhibitors; the answers to these questions may be a turning point in cancer therapy research.     

Biomarkers for the lung cancer diagnosis and their advances in proteomics

Over a last decade, intense interest has been focused on biomarker discovery and their clinical uses. This interest is accelerated by the completion of human genome project and the progress of techniques in proteomics. Especially, cancer biomarker discovery is eminent in this field due to its anticipated critical role in early diagnosis, therapy guidance, and prognosis monitoring of cancers. Among cancers, lung cancer, one of the top three major cancers, is the one showing the highest mortality because of failure in early diagnosis. Numerous potential DNA biomarkers such as hypermethylations of the promoters and mutations in K-ras, p53, and protein biomarkers; carcinoembryonic antigen (CEA), CYFRA21-1, plasma kallikrein B1 (KLKB1), Neuron-specific enolase, etc. have been discovered as lung cancer biomarkers. Despite extensive studies thus far, few are turned out to be useful in clinic. Even those used in clinic do not show enough sensitivity, specificity and reproducibility for general use. This review describes what the cancer biomarkers are for, various types of lung cancer biomarkers discovered at present and predicted future advance in lung cancer biomarker discovery with proteomics technology.     

Advances in proteomic prostate cancer biomarker discovery

Prostate cancer is the most common non-cutaneous cancer in men in the United States. For reasons largely unknown, the incidence of prostate cancer has increased in the last two decades, in spite or perhaps because of a concomitant increase in serum prostate-specific antigen (PSA) screening. While PSA is acknowledged not to be an ideal biomarker for prostate cancer detection, it is however widely used by physicians due to lack of an alternative. Thus, the identification of a biomarker(s) that can complement or replace PSA represents a major goal for prostate cancer research. Screening complex biological specimens such as blood, urine, and tissue to identify protein biomarkers has become increasingly popular over the last decade thanks to advances in proteomic discovery methods. The completion of human genome sequence together with new development in mass spectrometry instrumentation and bioinformatics has been a major driving force in biomarker discovery research. Here we review the current state of proteomic applications as applied to various sample sources including blood, urine, tissue, and “secretome” for the purpose of prostate cancer biomarker discovery. Additionally, we review recent developments in validation of putative markers, efforts at systems biology approach, and current challenges of proteomics in biomarker discovery.     

MicroRNAs: Potential biomarkers for cancer diagnosis,prognosis and targets for therapy

MicroRNAs have a revolutionary impact on cancer research over recent years. They emerge as important players in tumorigenesis, leading to a paradigm shift in oncology. The widespread and comprehensive use of microRNA microarrays has enabled the identification of a number of microRNAs as potential biomarkers for cancer. It is encouraging to report that microRNAs have remarkable stability in both formalin-fixed tissue and blood. Many microRNAs have been identified to act as oncogenes, tumor suppressors, or even modulators of cancer stem cells and metastasis. Some studies not only reported the identified microRNA biomarkers, but also deciphered their target genes and the underlying mechanisms. The rapid discovery of many microRNA targets and their relevant pathways has contributed to the development of microRNA-based therapeutics, but the developing progress of antisense or siRNA drugs has been hampered by stability, specificity and delivery problems. This review summarizes the most significant and latest findings of original researches on microRNAs involvement in cancer, focusing on the potential of cancer-related microRNAs as biomarkers for diagnosis, prognosis and targets for therapy.     

Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer

First described over 80 years ago, ataxia-telangiectasia (A-T) was defined as a clinical entity 50 years ago. Although not encountered by most clinicians, it is a paradigm for cancer predisposition and neurodegenerative disorders and has a central role in our understanding of the DNA-damage response, signal transduction and cell-cycle control. The discovery of the protein A-T mutated (ATM) that is deficient in A-T paved the way for rapid progress on understanding how ATM functions with a host of other proteins to protect against genome instability and reduce the risk of cancer and other pathologies.     

Integrative Proteomics and Tissue Microarray Profiling Indicate the Association between Overexpressed Serum Proteins and Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer deaths worldwide. Clinically, the treatment of non-small cell lung cancer (NSCLC) can be improved by the early detection and risk screening among population. To meet this need, here we describe the application of extensive peptide level fractionation coupled with label free quantitative proteomics for the discovery of potential serum biomarkers for lung cancer, and the usage of Tissue microarray analysis (TMA) and Multiple reaction monitoring (MRM) assays for the following up validations in the verification phase. Using these state-of-art, currently available clinical proteomic approaches, in the discovery phase we confidently identified 647 serum proteins, and 101 proteins showed a statistically significant association with NSCLC in our 18 discovery samples. This serum proteomic dataset allowed us to discern the differential patterns and abnormal biological processes in the lung cancer blood. Of these proteins, Alpha-1B-glycoprotein (A1BG) and Leucine-rich alpha-2-glycoprotein (LRG1), two plasma glycoproteins with previously unknown function were selected as examples for which TMA and MRM verification were performed in a large sample set consisting about 100 patients. We revealed that A1BG and LRG1 were overexpressed in both the blood level and tumor sections, which can be referred to separate lung cancer patients from healthy cases.     

Small molecule compounds targeting the p53 pathway: are we finally making progress?

Loss of function of p53, either through mutations in the gene or through mutations to other members of the pathway that inactivate wild-type p53, remains a critically important aspect of human cancer development. As such, p53 remains the most commonly mutated gene in human cancer. For these reasons, pharmacologic activation of the p53 pathway has been a highly sought after, yet unachieved goal in developmental therapeutics. Recently progress has been made not only in the discovery of small molecules that target wild-type and mutant p53, but also in the initiation and completion of the first in-human clinical trials for several of these drugs. Here, we review the current literature of drugs that target wild-type and mutant p53 with a focus on small-molecule type compounds. We discuss common means of drug discovery and group them according to their common mechanisms of action. Lastly, we review the current status of the various drugs in the development process and identify newer areas of p53 tumor biology that may prove therapeutically useful.     

Drug discovery from natural products

Natural product compounds are the source of numerous therapeutic agents. Recent progress to discover drugs from natural product sources has resulted in compounds that are being developed to treat cancer, resistant bacteria and viruses and immunosuppressive disorders. Many of these compounds were discovered by applying recent advances in understanding the genetics of secondary metabolism in actinomycetes, exploring the marine environment and applying new screening technologies. In many instances, the discovery of a novel natural product serves as a tool to better understand targets and pathways in the disease process. This review describes recent progress in drug discovery from natural sources including several examples of compounds that inhibit novel drug targets.