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The epithelial–mesenchymal transition (EMT) plays a critical role in embryonic development. EMT is also involved in cancer progression and metastasis and it is probable that a common molecular mechanism is shared by these processes. Cancer cells undergoing EMT can acquire invasive properties and enter the surrounding stroma, resulting in the creation of a favorable microenvironment for cancer progression and metastasis. Furthermore, the acquisition of EMT features has been associated with chemoresistance which could give rise to recurrence and metastasis after standard chemotherapeutic treatment. Thus, EMT could be closely involved in carcinogenesis, invasion, metastasis, recurrence, and chemoresistance. Research into EMT and its role in cancer pathogenesis has progressed rapidly and it is now hypothesized that novel concepts such as cancer stem cells and microRNA could be involved in EMT. However, the involvement of EMT varies greatly among cancer types, and much remains to be learned. In this review, we present recent findings regarding the involvement of EMT in cancer progression and metastasis and provide a perspective from clinical and translational viewpoints. (Cancer Sci 2009)

Understanding cancer evolution provides a clue to tackle therapeutic difficulties in colorectal cancer. In this review, together with related works, we will introduce a series of our studies, in which we constructed an evolutionary model of colorectal cancer by combining genomic analysis and mathematical modeling. In our model, multiple subclones were generated by driver mutation acquisition and subsequent clonal expansion in early-stage tumors. Among the subclones, the one obtaining driver copy number alterations is endowed with malignant potentials to constitute a late-stage tumor in which extensive intratumor heterogeneity is generated by the accumulation of neutral mutations. We will also discuss how to translate our understanding of cancer evolution to a solution to the problem related to therapeutic resistance: mathematical modeling suggests that relapse caused by acquired resistance could be suppressed by utilizing clonal competition between sensitive and resistant clones. Considering the current rate of technological development, modeling cancer evolution by combining genomic analysis and mathematical modeling will be an increasingly important approach for understanding and overcoming cancer.

Inflammation plays an essential role in the development and progression of most cancers. Chemokine C‐C motif chemokine 2 (CCL2) and its receptor C‐C chemokine receptor type 2 (CCR2) constitute a key signaling axis in inflammation that has recently attracted much interest on the basis of evidence showing its association with cancer progression. Propagermanium (3‐oxygermylpropionic acid polymer) is an organogermanium compound that is given for the treatment of hepatitis B in Japan and which inhibits the CCL2‐CCR2 signaling pathway. Herein, we review the importance of the CCL2‐CCR2 axis as a target in cancer treatment as shown by studies in mice and humans with pharmacological agents including propagermanium. The chemokine CCL2 and its receptor CCR2 constitute a key signaling axis in inflammation that has recently attracted much interest on the basis of evidence showing its association with cancer progression. Propagermanium (3‐oxygermylpropionic acid polymer) is an organogermanium compound that is given for the treatment of hepatitis B in Japan and which inhibits the CCL2‐CCR2 signaling pathway. Herein, we review the importance of the CCL2‐CCR2 axis as a target in cancer treatment as shown by studies in mice and humans with pharmacological agents including propagermanium.

The biological significance of micro (mi)RNAs has traditionally been evaluated according to their RNA expression levels based on the assumption that miRNAs recognize and regulate their targets in an unvarying fashion. Here we show that a fraction of mature miRNAs including miR-17-5p, -21-5p, and -200c-3p and let-7a-5p harbor methyl marks that potentially alter their stability and target recognition. Importantly, methylation of these miRNAs was significantly increased in cancer tissues as compared to paired normal tissues. Furthermore, miR-17-5p methylation level in serum samples distinguished early pancreatic cancer patients from healthy controls with extremely high sensitivity and specificity. These findings provide a basis for diagnostic strategies for early-stage cancer and add a dimension to our understanding of miRNA biology. In cancer it is assumed that microRNAs recognise and regulate their targets uniformly. Here, the authors show that in gastrointestinal cancers methylation of microRNAs may impact their stability, and that levels of microRNA methylation are distinct in pancreatic cancer patients compared to healthy controls with potential diagnostic implications.

Cancer is composed of multiple cell populations with different genomes. This phenomenon called intratumor heterogeneity (ITH) is supposed to be a fundamental cause of therapeutic failure. Therefore, its principle‐level understanding is a clinically important issue. To achieve this goal, an interdisciplinary approach combining genome analysis and mathematical modeling is essential. For example, we have recently performed multiregion sequencing to unveil extensive ITH in colorectal cancer. Moreover, by employing mathematical modeling of cancer evolution, we demonstrated that it is possible that this ITH is generated by neutral evolution. In this review, we introduce recent advances in a research field related to ITH and also discuss strategies for exploiting novel findings on ITH in a clinical setting. In this review, we introduce recent findings on intratumor heterogeneity (ITH) revealed by genome analysis and mathematical modeling and also discuss treatment strategies based upon ITH in a clinical setting.

Cancer is a leading cause of death worldwide, and the incidence continues to increase. Despite major research aimed at discovering and developing novel and effective anticancer drugs, oncology drug development is a lengthy and costly process, with high attrition rates. Drug repositioning (DR, also referred to as drug repurposing), the process of finding new uses for approved noncancer drugs, has been gaining popularity in the past decade. DR has become a powerful alternative strategy for discovering and developing novel anticancer drug candidates from the existing approved drug space. Indeed, the availability of several large established libraries of clinical drugs and rapid advances in disease biology, genomics/transcriptomics/proteomics and bioinformatics has accelerated the pace of activity‐based, literature‐based and in silico DR, thereby improving safety and reducing costs. However, DR still faces financial obstacles in clinical trials, which could limit its practical use in the clinic. Here, we provide a brief review of DR in cancer and discuss difficulties in the development of DR for clinical use. Furthermore, we introduce some promising DR candidates for anticancer therapy in Japan. We provide a brief review of drug repositioning (DR) in cancer and discuss difficulties in the development of DR for clinical use. Furthermore, we introduce some promising DR candidates for anticancer therapy in Japan.

Alternative splicing, regulated by DEAD‐Box Helicase (DDX) families, plays an important role in cancer. However, the relationship between the DDX family and cancer has not been fully elucidated. In the present study, we identified a candidate oncogene DDX56 on Ch.7p by a bioinformatics approach using The Cancer Genome Atlas (TCGA) dataset of colorectal cancer (CRC). DDX56 expression was measured by RT‐qPCR and immunochemical staining in 108 CRC patients. Clinicopathological and survival analyses were carried out using three CRC datasets. Biological roles of DDX56 were explored by gene set enrichment analysis (GSEA), and cell proliferation in vitro and in vivo, cell cycle assays, and using DDX56‐knockdown or overexpressed CRC cells. RNA sequencing was carried out to elucidate the effect of DDX56 on mRNA splicing. We found that DDX56 expression was positively correlated with the amplification of DDX56 and was upregulated in CRC cells. High DDX56 expression was associated with lymphatic invasion and distant metastasis and was an independent poor prognostic factor. In vitro analysis, in vivo analysis and GSEA showed that DDX56 promoted proliferation ability through regulating the cell cycle. DDX56 knockdown reduced intron retention and tumor suppressor WEE1 expression, which functions as a G2‐M DNA damage checkpoint. We have identified DDX56 as a novel oncogene and prognostic biomarker of CRC that promotes alternative splicing of WEE1. We identified DDX56 as a novel oncogene on chromosome 7p and a prognostic biomarker of colorectal cancer (CRC). DDX56 can induce oncogenic splicing abnormalities of the G2‐M cell cycle checkpoint gene WEE1 which contributes to the inhibition of proliferation and cell cycle progression.

During the process of metastasis, which is the leading cause of cancer-related death, cancer cells dissociate from primary tumors, migrate to distal sites, and finally colonize, eventually leading to the formation of metastatic tumors. The migrating tumor cells in circulation, e.g., those found in peripheral blood (PB) or bone marrow (BM), are called circulating tumor cells (CTCs). CTCs in the BM are generally called disseminated tumor cells (DTCs). Many studies have reported the detection and characterization of CTCs to facilitate early diagnosis of relapse or metastasis and improve early detection and appropriate treatment decisions. Initially, epithelial markers, such as EpCAM and cytokeratins (CKs), identified using immunocytochemistry or reverse transcription polymerase chain reaction (RT-PCR) were used to identify CTCs in PB or BM. Recently, however, other markers such as human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and immuno-checkpoint genes also have been examined to facilitate detection of CTCs with metastatic potential. Moreover, the epithelial-to-mesenchymal transition (EMT) and cancer stem cells (CSCs) have also received increasing attention as important CTC markers owing to their roles in the biological progression of metastasis. In addition to these markers, researchers have attempted to develop detection or capture techniques for CTCs. Notably, however, the establishment of metastasis requires cancer-host interactions. Markers from host cells, such as macrophages, mesenchymal stem cells, and bone marrow-derived cells, which constitute the premetastatic niche, may become novel biomarkers for predicting relapse or metastasis or monitoring the effects of treatment. Biological studies of CTCs are still emerging. However, recent technical innovations, such as next-generation sequencing, are being used more commonly and could help to clarify the mechanism of metastasis. Additionally, biological findings are gradually being accumulated, adding to our body of knowledge on CTCs. In this review, we will summarize recent approaches to detect or capture CTCs. Moreover, we will introduce recent studies of the clinical and biological importance of CTCs and host cells. •Clinical and biological characteristics of circulating tumor cells (CTCs) are gradually being accumulated.•Development of sensitive and useful detection technologies of CTCs is ongoing.•Novel host-side markers FBXW7/CCL2 for predicting cancer metastasis are proposed.•Targeting CTCs markers would be the most successful therapeutic strategy to eliminate cancer cells with metastatic potential.