Circulating tumor cells as therapy-related biomarkers in cancer patients

Carcinomas (tumors of epithelial origin) are responsible for most of all new cancers in the industrialized countries. Due to the high mortality rate caused by the metastatic spread of aggressive cancer cells, there is an urgent demand in finding new biomarkers, which should detect early formation of metastases and monitor efficacy of systemic adjuvant therapy in a timely manner. It has been considered that the molecular analysis of cells which are shed from tumors into the blood system (circulating tumor cells (CTCs)) might provide new insights for the clinical management of cancer, probably far earlier than using traditional high-resolution imaging technologies. Clinical trials indicated that CTCs can be deployed for diagnostic, monitoring, and prognostic purposes. Furthermore, these cells are discussed to be suitable as predictive markers. In any case, identification of CTCs requires innovative and challenging technologies as detection methods should be specific, sensitive, standardized, and highly reproducible. Although many different approaches have been developed until now, only the CellSearch? method has been cleared by the American Food and Drug Administration. Although the detection of CTCs has already shown to have a prognostic impact in many tumor entities including breast, prostate, lung and colon cancer, ongoing and future studies are aimed to explore whether CTCs can be used for an individual therapy decision making including novel immunotherapeutic approaches. This review discusses (1) different detection strategies for CTCs, (2) their clinical impact, and (3) the potential use of CTCs guiding the treatment of individual cancer patients.     

Circulating miRNA and cancer diagnosis

miRNAs are a class of small RNA molecules with regulatory function, and play an important role in tumor development and progression. It has been demonstrated that tumor-derived miRNAs exist in the circulating nucleic acids of cancer patients. This phenomenon implies that detection of the circulating miRNA may be an effective method for non-invasive diagnosis of cancer. In this review, we summarize the applications of the circulating miRNA as biomarkers in cancer diagnosis, as well as the latest research progress in this area.     

循环长链非编码RNA作为生物标志物在肿瘤分子诊断中的应用

长链非编码RNA(Long noncoding RNA,lncRNA)被发现广泛参与基因表达、表观遗传调控和X染色体失活等重要生命过程,还与肿瘤发生和发展密切相关。lncRNA可能以微泡、外泌体或蛋白质复合物形式进入人体循环系统中,形成循环lncRNA稳定而广泛存在于血液、尿液等体液中。文中简要回顾了近来关于循环lncRNA的来源,以及作为生物标志物的检测方法,着重总结分析了循环lncRNA作为潜在肿瘤生物标志物在肺癌、乳腺癌、胃癌、肝癌、结直肠癌和前列腺癌等常见恶性肿瘤中的早期诊断价值。与传统生物标志物相比,循环lncRNA具有作为新型生物标志物的独特优势和临床应用价值。     

Circulating tumor cells in the early detection of human cancers

Cancer is a severe disease with high morbidity and mortality globally. Thus, early detection is emerging as an important topic in modern oncology. Although the strategies for early detection have developed rapidly in recent decades, they remain challenging due to the subtle symptoms in the initial stage of the primary tumor. Currently, tumor biomarkers, imaging, and specific screening tests are widely used in various cancer types; however, each method has limitations. The harms are even overweight against the benefits in some cases. Therefore, early detection approaches should be improved urgently. Liquid biopsy, for now, is a convenient and non-invasive way compared to the traditional tissue biopsy in screening and early diagnosis. Circulating tumor cells (CTCs) are vital in liquid biopsy and play a central role in tumor dissemination and metastases. They have promising potential as cancer biomarkers in early detection. This review updates the knowledge of the biology of CTC; it also highlights the CTC enrichment technologies and their applications in the early detection of several human cancers.     

Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer

Pancreatic adenocarcinoma is currently the fourth leading cause for cancer-related mortality. Stem cells have been implicated in pancreatic tumor growth, but the specific role of these cancer stem cells in tumor biology, including metastasis, is still uncertain. We found that human pancreatic cancer tissue contains cancer stem cells defined by CD133 expression that are exclusively tumorigenic and highly resistant to standard chemotherapy. In the invasive front of pancreatic tumors, a distinct subpopulation of CD133(+) CXCR4(+) cancer stem cells was identified that determines the metastatic phenotype of the individual tumor. Depletion of the cancer stem cell pool for these migrating cancer stem cells virtually abrogated the metastatic phenotype of pancreatic tumors without affecting their tumorigenic potential. In conclusion, we demonstrate that a subpopulation of migrating CD133(+) CXCR4(+) cancer stem cells is essential for tumor metastasis. Strategies aimed at modulating the SDF-1/CXCR4 axis may have important clinical applications to inhibit metastasis of cancer stem cells.     

Targeted destruction of the orchestration of the pancreatic stroma and tumor cells in pancreatic cancer cases: Molecular basis for therapeutic implications

Pancreatic cancer is one of the most lethal malignancies, with a prominent desmoplastic reaction as its defining hallmark. The past several decades have seen dramatic progress in understanding of pancreatic cancer pathogenesis, including identification of precursor lesions, sequential transformation from normal pancreatic tissue to invasive pancreatic cancer and corresponding signature genetic events, and the biological impact of these events on malignant behavior. However, the currently used therapeutic strategies for epithelial tumor cells, which have exhibited potent antitumor activity in cell culture and animal models, have failed to produce significant effects in the clinic. The desmoplastic stroma surrounding pancreatic cancer cells, which accounts for about 90% of a tumor's mass, clearly is not a passive scaffold for cancer cells but an active contributor to carcinogenesis. Improved understanding of the dynamic interaction between cancer cells and the stroma will be important to designing effective therapeutic strategies for pancreatic cancer. This review focuses on the origin of stromal molecular and cellular components in pancreatic tumors, their biological effects on pancreatic cancer cells, and the orchestration of these two components.     

Circulating tumor cells: approaches to isolation and characterization

Circulating tumor cells (CTCs) shed from primary and metastatic cancers are admixed with blood components and are thus rare, making their isolation and characterization a major technological challenge. CTCs hold the key to understanding the biology of metastasis and provide a biomarker to noninvasively measure the evolution of tumor genotypes during treatment and disease progression. Improvements in technologies to yield purer CTC populations amenable to better cellular and molecular characterization will enable a broad range of clinical applications, including early detection of disease and the discovery of biomarkers to predict treatment responses and disease progression.     

Circulating tumor cells: the 'leukemic phase' of solid cancers

It is well known that malignant cells circulate in the bloodstream of patients with solid tumors. However, the biological significance of circulating tumor cells (CTCs) and the clinical relevance of their detection are still debated. Besides technical issues regarding CTC-detection methods, discontinuous shedding of CTCs from established cancer deposits, genomic instability and metastatic inefficiency might underlie the conflicting results currently available. Nevertheless, technological advances and recent clinical findings are prompting researchers to dissect CTC biology further. Here, we review these recent findings, and discuss the prospects for the identification and molecular characterization of the CTC subset that is responsible for metastasis development. This would provide a formidable tool for prognosis evaluation, anticancer-drug development and, ultimately, cancer-therapy personalization.     

Relationships of hepatic and pancreatic biomarkers with the cholestatic syndrome and tumor stage in pancreatic cancer

We analyzed relationships of hepatic and pancreatic biomarkers with the cholestatic syndrome and tumor stage in exocrine pancreatic cancer (N = 183). Information on laboratory tests and on signs and symptoms was obtained from medical records and patient interviews. Bilirubin, aspartate aminotransferase (AST), γ-glutamyltransferase (GGT) and alkaline phosphatase were lower in tumor stage IV. The association was due to the relationship between cholestatic syndrome and earlier presentation of patients. There was no association between hepatic biomarkers and stage when adjusting by cholestatic syndrome. Relationships of hepatic and pancreatic biomarkers with pancreatic symptoms and tumor stage must be controlled in "-omics" and other studies using biomarkers.     

Relationships of hepatic and pancreatic biomarkers with the cholestatic syndrome and tumor stage in pancreatic cancer

We analyzed relationships of hepatic and pancreatic biomarkers with the cholestatic syndrome and tumor stage in exocrine pancreatic cancer (N = 183). Information on laboratory tests and on signs and symptoms was obtained from medical records and patient interviews. Bilirubin, aspartate aminotransferase (AST), γ-glutamyltransferase (GGT) and alkaline phosphatase were lower in tumor stage IV. The association was due to the relationship between cholestatic syndrome and earlier presentation of patients. There was no association between hepatic biomarkers and stage when adjusting by cholestatic syndrome. Relationships of hepatic and pancreatic biomarkers with pancreatic symptoms and tumor stage must be controlled in “-omics” and other studies using biomarkers.     

Circulating tumor cells: highlight on practical implications

Circulating tumor cells (CTCs) are cells of presumed epithelial origin, whose prognostic and predictive value in metastatic cancer patients has recently been demonstrated. To date, the count of CTCs through the CellSearch? system represents a valid approach for monitoring disease status in patients with metastatic colorectal, breast, and prostate cancer; in these cancer types, a rise in the CTC count at any time during treatment predicts a poor outcome. Nevertheless, the clinical utility of monitoring CTC counts remains controversial, and what to do when CTC counts rise during therapy still remains an unanswered question. In this report, we suggest how to integrate CTC counts with their molecular characterization to better translate biologic information obtained on CTCs into daily clinical practice.     

Imaging in the diagnosis and management of prostate cancer

The current diagnosis and management of prostate cancer is largely based on the use of serum prostate-specific antigen (PSA) and pathologic risk factors such as Gleason score and clinical stage. The use of serum PSA in clinical practice has resulted in significant stage migration and, as such, imaging modalities historically utilized to stage prostate cancer are no longer able to reliably identify the small amounts of prostate cancer most often found at presentation. Molecular imaging techniques have focused on improving sensitivity and specificity for cancer detection through knowledge of specific attributes of disease biology. The evolution of imaging techniques has created a new role for imaging in the management of prostate cancer.