Role In Metastatic Cascade Research Articles

Circulating Tumor Cells as a Tool to Untangle the Breast Cancer Heterogeneity Issue.

Breast cancer (BC) is a disease characterized by high degrees of heterogeneity at morphologic, genomic, and genetic levels, even within the same tumor mass or among patients. As a consequence, different subpopulations coexist and less represented clones may have a selective advantage, significantly influencing the outcome of BC patients. Circulating tumor cells (CTCs) represent a rare population of cells with a crucial role in metastatic cascade, and in recent years have represented a fascinating alternative to overcome the heterogeneity issue as a “liquid biopsy”. However, besides the raw enumeration of these cells in advanced epithelial tumors, there are no CTC-based assays applied in the clinical practice to improve personalized medicine. In this review, we report the latest findings in the field of CTCs for intra-tumoral heterogeneity unmasking in BC, supporting the need to deepen their analysis to investigate their role in metastatic process and include the molecular characterization in the clinical practice. In the future, CTCs will be helpful in monitoring patients during treatment, as well as to better address therapeutic strategies.

CIRCULATING TUMOR CELLS: WHERE WE LEFT OFF?

Cancer metastasis and recurrence are the leading causes of cancer-related death. Tumor cells which leave the primary or secondary tumors and shed into the bloodstream are called circulating tumor cells (CTC). These cells are the key drivers of cancer dissemination to surrounding tissues and to distant organs. The use of CTC in clinical practice necessitates the deep insight into their biology, as well as into their role in cancer evasion of immune surveillance, tumor resistance to chemo- radio- and immunotherapies and metastatic dormancy. Aim. The purpose of the work was to review the current knowledge on the CTC biology, as well as the prospects for their use for the diagnosis and targeted treatment of metastatic disease. Methods. The work proposed the integrative literature review using MEDLINE, Biological Abstracts and EMBASE databases. Results. This review summarizes and discusses historical milestones and current data concerning СTС biology, the main stages of their life cycle, their role in metastatic cascade, clinical prospects for their use as markers for the diagnosis and prognostication of the disease course, as well as targets for cancer treatment. Conclusions. Significant progress in the area of CTC biology and their use in cancer theranostics convincingly proved the attractiveness of these cells as targets for cancer prognosis and therapy. The effective use of liquid biopsy with quantitative and phenotypic characteristics of CTCs is impeded by the imperfection of the methodology for taking biological material and by the lack of reliable markers for assessing the metastatic potential of CTCs of various origins. The variety of mechanisms of tumor cells migration and invasion requires the development of complex therapeutic approaches for anti-metastatic therapy targeting CTCs. Efforts to address these key issues could help developing new and effective cancer treatment strategies.

Abstract B29: The elucidation for functional roles of Metadherin in metastatic cascade of pancreatic cancer

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. At present, surgical resection is the only curative treatment for PDAC, but the majority of PDAC patients show early recurrence even after curative resection. There is a possibility of having been distant micrometastasis at early stage of carcinogenesis in PDAC. The control of PDAC metastatic progression leads to improve the prognosis of PDAC patients. Recently, it is reported that a verified mediator of distant metastasis, Metadherin (MTDH), promotes metastasis in experimental models of breast cancer, and its high expression is associated with poor prognosis in a large spectrum of cancer types. Recent evidences imply that the epithelial-mesenchymal transition (EMT) and putative cancer stem cell (CSC) functions orchestrates to play crucial roles in cancer progression. In this study, we aim to investigate the function of MTDH in PDAC progression concomitant with undergoing EMT/MET plasticity or involving putative CSC functions. Experimental methods: We investigated MTDH expression in 7 human and 6 mouse PDAC cell lines and elucidated the roles of MTDH in PDAC progression by in vitro experiments for the loss of function using siMTDH and shMTDH. In immunohistochemical (IHC) staining of MTDH in resected PDAC tissues, we analyzed the correlation between MTDH expression and the clinico-pathological parameters as well as clinical outcome of the 82 PDAC patients. Results: Western blot analyses showed higher MTDH protein expression in metastatic PDAC compared to primary PDAC cell lines. In metastatic cell lines, MTDH expression has a positive correlation with E-cadherin expression. These data suggest that MTDH might be related to mesenchymal-epithelial transition (MET) and play a crucial role in metastatic cascade of PDAC. Conversely, MTDH has a negative correlation with E-cadherin in primary PDAC cell lines. It is implicated that MTDH might play inverse functions in primary site and metastatic site. Next, to examine what is the role of MTDH in the EMT/MET process, we evaluated the expression pattern of EMT markers and MTDH in response to transient TGF-β1 treatment. We found that E-cadherin expression decreases at 8 to 24 hours after treatment (EMT initiation), and then comes back to increase of the expression at 4 days after treatment (MET induction). While MTDH and E-cadherin expression shows an inverse relation during EMT initiation, these two expressions have a positive correlation during MET period (from 7 days after treatment). Additionally, we found EMT induction by TGF-β1 is attenuated by knockdown of MTDH, These results suggest MTDH might contribute to the phenotypic switch of PDAC cells via the EMT/MET process. MTDH knockdown significantly impaired the ability of pancreatosphere formation in PDAC cells and sensitized PDAC cells to gemcitabine. In FACS analyses, we also found that the percentage of CD133-positive cancer stem cell subpopulation was significantly reduced in MTDH knockdown metastatic PDAC cells. In anoikis assay, (this assay evaluate the resistance for apoptosis after losing contact from extracelluar matrix), MTDH knockdown reduced anoikis resistance in PDAC cells. These data indicate that MTDH might foster putative CSC functions in PDAC cells. In IHC staining, high MTDH expression indicated significantly higher incidence of hematogenous metastasis (p=0.02). Furthermore, High expression group showed poorer prognosis of PDAC patients compared to Low expression group in Kaplan Meier analysis (p=0.029). Conclusions: MTDH might promote PDAC metastasis to undergo EMT in primary PDAC and MET in metastatic PDAC along with.putative CSC functions. The regulation of MTDH might develop the new strategy for PDAC treatment, and lead to improve the outcome of patients. Citation Format: Kensuke Suzuki, Shigetsugu Takano, Hideyuki Yoshitomi, Shingo Kagawa, Hiroaki Shimizu, Masayuki Otsuka, Katunori Furukawa, Tukasa Takayashiki, Satoshi Kuboki, Daisuke Suzuki, Nozomu Sakai, Hiroyuki Nojima, Masaru Miyazaki.{Authors}. The elucidation for functional roles of Metadherin in metastatic cascade of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B29.

Advances in the study of miRNA in metastasis of pancreatic cancer

Metastasis of pancreatic cancer is a multi-step, multi-stage and multi-approach complicated process involved in multiple gene changes. That is called cascade, including epithelial-mesenchymal transition, extracellular matrix and basement membrane degradation, tumor cells increased exercise capacity and the formation of tumor angiogenesis, intravasation and extravasation etc. In recent years, studies have found that miRNA play an important role in metastasis cascade. Key words: miRNA; Pancreatic neoplasms; Neoplasm metastasis

Prognostic and Predictive Role of Circulating Tumor Cells in Breast Cancer

Circulating tumor cells (CTCs) play a crucial role in metastatic cascade, tumor dissemination, and progression. CTCs represent a unique biomarker, as they are cancer cells and sampling of a patient's tumor. CTCs are a heterogeneous cell population of tumor cells with different phenotypes and biological values, with established prognostic impact in primary and metastatic breast cancer. Detection and molecular profiling of CTCs could represent a valuable prognostic and predictive factor, a tool for tumor ‘liquid’ biopsy in real time and for personalized anticancer treatment. Several trials are ongoing aimed to demonstrate clinical utility of CTCs detection and profiling to facilitate rational treatment decisions for breast cancer patients. Therapeutic targeting of CTCs might be a promising strategy to interfere with metastatic cascade and tumor dissemination.

Altered CD44 Variant 6 Expression in FIGO Stage IB Cervical Carcinoma

Objective. CD44 is an adhesion molecule which plays an important role in metastatic cascade by mediating tumor cell interaction with the endothelium and the subendothelial matrix. In this study CD44v6 expression was immunohistochemically investigated on 88 uterine cervical cancers. Correlation between expression and prognostic variables and the survival was examined.Methods. Eighty-eight patients with stage IB disease, treated primarily with surgery, were examined histopathologically and immunohistochemically. CD44v6 expressions of tumoral tissue and the nonneoplastic tissue nearby were examined using antiCD44v6 monoclonal antibody. CD44v6 expression was compared to the known clinicopathologic prognostic variables and survival of patients.Results. Nonneoplastic epithelium of the sections showed CD44v6 expression predominantly in basal and parabasal layers at least in traces. CD44v6 overexpression in neoplastic islands was evaluated as “general,” “basal” (only in the basal portion of neoplastic islands), and “nonbasal” (also in the central portion of the neoplastic islands) separately. When expression and prognostic variables were compared, CD44v6 non-basal expression was found to be significant in nonsquamous cancers, when the tumor diameter was greater than 3 cm and in the tumors that showed recurrences. Univariate survival analysis with the Kaplan–Meier method showed that only the age of the patient is significantly correlated with disease-free survival. Interestingly when the same analysis was done for 5-year overall survival, diameter of the primary tumor, depth of cervical stromal invasion, existence and number of lymph node involvement, positivity for general CD44v6 expression, and positivity for nonbasal expression were found to be statistically significant. Furthermore multivariate analysis with Cox regression showed that nonbasal CD44v6 expression and lymph node involvement are independent variables for 5-year overall survival.Conclusion. These results indicate that CD44v6 expression is associated with some of the important clinicopathologic prognostic variables and appears to be a predictor of advanced pathological–surgical stage of early clinical stage cervical carcinoma. CD44v6 nonbasal expression is significantly correlated with overall survival.