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Cancer has a character of heterogeneity, which makes it difficult to determine treatment strategy and predict prognosis. To conquer this problem, comprehensive analyses have been actively performed for gene expression, and molecular subtypes of various types of cancer have been identified by many studies. In colorectal cancer(CRC), there are known to be other subtypes than gene expression, that is, chromosome instability(CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP). Classification of molecular subtypes by integrating these multiple biological properties would realize the effective tailor-made treatment, and improve CRC patient's prognosis. In this article, we overview the mechanisms of CRC carcinogenesis, and present the latest biological classification of subtypes in CRC.

Although cancer is a genetic disease, epigenetic alterations are involved in its initiation and progression. Previous studies showed that the introduction of endogenous small-sized, noncoding ribonucleotides including microRNA200c, -302s, and -369 resulted in the induction of cellular reprogramming. MicroRNA200c inhibits the epithelial-mesenchymal transition. MicroRNA302s induces the demethylation of the tumor suppressor gene promoter region, while microRNA369 changes cancer cell metabolism. These three types of microRNA induce cancer cellular reprogramming and modulate malignant phenotypes of human cancer cells. These results suggest that the appropriate delivery of functional small-sized ribonucleotides may be a novel approach to the treatment of human cancer.

Cancer has been viewed as a heterogeneous population of cells.While the large majority of cells that constituting tumors are differentiated, and eventually stop dividing, only a minority population of cells, termed cancer stem cells, is capable of unlimited self-renewal and multi-differentiation, just like somatic stem cells in normal tissues.Cancer stem cells have been identified in a variety of cancers of the blood, brain, stomach, colon, and pancreas.In this review we present current evidence supporting the cancer stem cell model of tumor progression, and discuss the experimental and therapeutic implications.

Cancer metabolism characterizes the malignant behavior of tumors. Pyruvate kinase M2 (PKM2), a key player in maintaining aerobic glycolysis, stimulates tumor growth by controlling the Warburg effect. It has been shown that PKM2 translocates into the nucleus to regulate the transcriptions of numerous down-stream genes, including PDK1 and LDHA. To investigate the significance of PKM2 in epithelial-mesenchymal transition (EMT), a biological process which promotes the metastasis of cancer cells, we induced EMT in gastrointestinal cancer cells using TGFβ and EGF in vitro. After EMT induction, E-cadherin was down-regulated, whereas Vimentin was up-regulated. PKM2 expression was increased at both the transcriptional and the translational level, and PKM2 translocated into the nucleus. Immunohistochemical staining of PKM2 revealed that PKM2 positivity correlated significantly with lymph node metastasis and distant organ metastasis of gastrointestinal cancer. The present results indicate that nuclear PKM2 plays a crucial role in controlling invasion and metastasis.

Cancer stem cells are known to influence survival, chemoresistance, relapse and metastasis. Pyruvate kinase M2 (PKM2) maintains aerobic glycolysis in cancer cells and stimulates cell proliferation by controlling Warburg effect. In addition, PKM2 translocates to nucleus and up-regulates PDK1 expression by controlling its transcription. PKM2 confers malignant potential by controlling both metabolism and transcriptional regulation. Tumor invasion is initiated with the change of epithelial-mesenchymal transition (EMT) in cancer cell. After EMT induction, in parallel with E-cadherin down-regulation and vimentin up-regulation, the expression of PKM2 was increased both in transcriptional and translational level and PKM2 translocated into nucleus. TGIF2 was identified which interacted with PKM2 in nucleus in response to EMT induction, which was considered to have a key role in controlling EMT induction. We performed immunohistochemical staining with specific antibody to PKM2 using clinical samples of colorectal cancers. Clinicopathological analysis showed that PKM2 positivity significantly correlated with lymph node metastasis and distant organ metastasis. In conclusion, our data suggested that PKM2 nuclear function had a crucial role in controlling invasion and metastasis.

It is considered that cancer stem cells have the same characteristics as normal stem cells, such as drug-resistance, self-renewal, differentiation, and tissue-formation. Normal stem cells depend on their surroundings, a niche. Cancer stem cells may also depend on their own niche. Because cancer stem cells are resistant to present remedies, it is important to find a remedy targeting cancer stem cells. The remedy must not only target cancer stem cells themselves but also target the niche surrounding the cancer stem cells.