Positive selection in the evolution of cancer

We hypothesize that forms of antagonistic coevolution have forged strong links between positive selection at the molecular level and increased cancer risk. By this hypothesis, evolutionary conflict between males and females, mothers and foetuses, hosts and parasites, and other parties with divergent fitness interests has led to rapid evolution of genetic systems involved in control over fertilization and cellular resources. The genes involved in such systems promote cancer risk as a secondary effect of their roles in antagonistic coevolution, which generates evolutionary disequilibrium and maladaptation. Evidence from two sources: (1) studies on specific genes, including SPANX cancer/testis antigen genes, several Y-linked genes, the pem homebox gene, centromeric histone genes, the breast cancer gene BRCA1, the angiogenesis gene ANG, cadherin genes, cytochrome P450 genes, and viral oncogenes; and (2) large-scale database studies of selection on different functional categories of genes, supports our hypothesis. These results have important implications for understanding the evolutionary underpinnings of cancer and the dynamics of antagonistically-coevolving molecular systems.     

转录因子Snail的作用机制及其生理功能

Snail为起负调节作用的锌指转录因子,其序列和功能在不同种属动物中十分保守。Snail超家族成员在胚胎着床、胚胎发生、肿瘤发生、细胞命运决定、细胞周期调控、左右不对称发育及创伤愈合等生理或病理过程发挥重要作用。对Snail的进一步研究,不仅可以阐明Snail超家族的作用机制,而且可以为探究Snail相关的肿瘤治疗策略提供重要的理论基础。     

E-cadherin 在肿瘤治疗中的研究进展

E-cadherin 参与形成细胞间黏附性连接,是胚胎发育过程中的一个关键因子。越来越多的研究表明,E-cadherin 在肿瘤的发生发 展过程中也发挥了至关重要的作用。在生物体内,E-cadherin 的表达和功能受到多个水平、多重因素的调控,而 E-cadherin 又可以影响 多条重要信号通路的活性,参与到多种生理病理过程中。E-cadherin 下调造成细胞间黏附性连接减少、极性减弱,细胞由上皮样转变为间 质样,这一变化是上皮间质转化（EMT）的重要标志之一。E-cadherin 与多种肿瘤的发生有一定的相关性。同时 E-cadherin 下调所引起 的 EMT 促进肿瘤细胞的迁移运动,肿瘤细胞侵袭力增强,促进转移的发生。近年来,大量研究关注到 E-cadherin 对肿瘤细胞的耐药及干 细胞特性的获得都有影响。综述 E-cadherin 在肿瘤发生发展中的作用,探讨以 E-cadherin 为靶点的肿瘤治疗的现状及展望。     

Trifluoperazine as an alternative strategy for the inhibition of tumor growth of colorectal cancer

The development of cancer in patients with schizophrenia is affected by genetic and environmental factors and antipsychotic medication. Several studies found that schizophrenia was associated with decreased risk of some cancers, and the neuroleptic medication might help to reduce the risk of colorectal cancer (CRC). Phenothiazine drugs including trifluoperazine (TFP) are widely used antipsychotic drugs and showed some antitumor effects, we here investigated the potential application of TFP in the treatment of colon cancer. A series doses of TFP were treated to the colon cancer cell line HCT116 and the inhibitory concentration (IC₅₀) of TFP for HCT116 was determined by cell counting kit-8. The results indicated that the treatment of TFP impaired the cell vitality of HCT116 in a dose- and time-dependent manner. Meanwhile, the Edu assay demonstrated that the proliferation was also inhibited by TFP, which was accompanied with the induction of apoptosis and autophagy. The expression of CCNE1, CDK4, and antiapoptosis factor BCL-2 was downregulated but the proapoptosis factor BAX was upregulated. The autophagy inhibitor chloroquine could significantly reverse the TFP-induced apoptosis. Moreover, the ability of migration and invasion of HCT116 was found to be suppressed by TFP, which was associated with the inhibition of epithelial-mesenchymal transition (EMT). The function of TFP in vivo was further confirmed. The results showed that the administration of TFP remarkably abrogated the tumor growth with decreased tumor volume and proliferation index Ki-67 level in tumor tissues. The EMT phenotype was also confirmed to be inhibited by TFP in vivo, suggesting the promising antitumor effects of TFP in CRC.     

New insights of epithelial-mesenchymal transition in cancer metastasis

Epithelial-mesenchymal transition (EMT) is a key step during embryonic morphogenesis, heart development, chronic degenerative fibrosis, and cancer metastasis. Several distinct traits have been conveyed by EMT, including cell motility, invasiveness, resistance to apoptosis, and some properties of stem cells. Many signal pathways have contributed to the induction of EMT, such as transforming growth factor-β, Wnt, Hedgehog, Notch, and nuclear factor-κB. Over the last few years, increasing evidence has shown that EMT plays an essential role in tumor progression and metastasis. Understanding the molecular mechanism of EMT has a great effect in unraveling the metastatic cascade and may lead to novel interventions for metastatic disease.     

Associations between the cyclooxygenase-2 expression in circulating tumor cells and the clinicopathological features of patients with colorectal cancer

While previous studies have shown that the number of circulating tumor cells (CTCs) alone is not sufficient to reflect tumor progression and that cyclooxygenase-2 (COX-2) expression is correlated with colorectal cancer (CRC) metastasis, COX-2 expression status and its potential functions in CTCs of CRC patients are unknown. Here, epithelial-mesenchymal transition (EMT) phenotype-based subsets of CTCs and the COX-2 expression status in CTCs were identified and their potential clinical values were assessed in 91 CRC patients. CTCs were enumerated in peripheral blood and subsets of CTCs (epithelial [eCTCs], mesenchymal [mCTCs], and biophenotypic [bCTCs]) and the COX-2 expression status were determined using the RNA in situ hybridization method. CTCs were detected in 80.2% (73 of 91) patients. Neither the total CTC nor eCTC numbers were found to significantly associate with any of the clinicopathological features. However, the number of mCTCs was significantly associated with distance metastasis (P = 0.035) and had a trend of being associated with lymph node metastasis ( P = 0.055). Among the 73 patients enrolled for evaluating COX-2 expression, 52.5% (38 of 73) were found to express COX-2 in CTCs, and COX-2 expression in CTCs was not found to associate with the clinicopathological factors. However, COX-2 expression in mCTCs tended to have a higher rate in patients with metastasis compared with those without metastasis (72.0% vs 42.8%; P = 0.072). Furthermore, COX-2 expression and mCTC marker expression correlated positively ( R = 0.287; P = 0.017). Further studies are required to investigate the clinical value of the expression of COX-2 in mCTCs, especially in CRC patients with the advanced tumor stage and distant metastasis.     

基质金属蛋白酶在乳腺癌上皮间质转化中的作用

基质金属蛋白酶(matrix metalloproteinase,MMP)能够分解并修饰细胞外基质及细胞连接,促进上皮细胞从周围组织中分离出来。在乳腺癌中MMP表达量升高,刺激肿瘤发生,引起癌症细胞的入侵和转移。上皮细胞-间质细胞转化(epithelial-mesenchymal transition,EMT)的激活与肿瘤的发生也有关。最近的研究表明MMP在乳腺的发育和致病的EMT过程中充当促进因子和介质的角色。本文主要概括最新的关于MMP是如何调节乳腺癌细胞的运动、入侵和EMT所驱动的乳腺癌发育的研究,为更好地理解MMP在乳腺癌发病过程中的作用提供依据。     

HDAC2 promotes the EMT of colorectal cancer cells and via the modular scaffold function of ENSG00000274093.1

Histone deacetylase 2 (HDAC2), a member of the Histone deacetylase family, plays a vital role in various carcinomas. In this study, we identified that HDAC2 expression levels are associated with liver metastasis, higher T stages and poor prognosis in colorectal cancer. HDAC2 down-regulation via lentivirus-mediated expression of HDAC2-targeting shRNA reduced the in vitro migration and invasion ability of HCT116 cell as well as their liver metastasis in nude mouse xenografts. Mechanistically, HDAC2 promotes epithelial-mesenchymal transition (EMT) in colorectal cancer cells by combining HDAC1 with EZH2 (a key histone methyltransferase), possibly through the modular scaffold function of a new lncRNA, ENSG00000274093.1. HDAC2 thus appears to promote CRC cell migration and invasion through binding HDAC1 and EZH2 via ENSG00000274093.1.     

Peritumoral monocytes induce cancer cell autophagy to facilitate the progression of human hepatocellular carcinoma

Macroautophagy/autophagy is an important catabolic process mediating cellular homeostasis and plays critical roles in cancer development. Whereas autophagy has been widely studied in various pathological models, little is known about the distribution, clinical significance and regulatory mechanism of this process in human hepatocellular carcinoma (HCC). In the present study, we found that tumor tissues exhibited significantly increased levels of autophagy compared with non-tumor tissues, and cancer cells with higher levels of autophagy were predominantly enriched in the invading edge regions of human HCC. Increased MAP1LC3B/LC3B expression in the invading edge regions was significantly correlated with a higher density of closely located monocytes, and TNF and IL1B derived from tumor-activated monocytes synergistically induced cancer cell autophagy in the invading edge regions of HCC. Monocyte-elicited autophagy induced the epithelial-mesenchymal transition (EMT) of cancer cells and promoted tumor metastasis by activating the NFKB-SNAI1 signaling pathway. Moreover, the increase of LC3B⁺ cancer cells in the invading edge areas was associated with high mortality and reduced survival of patients with HCC. These findings indicated that cancer cell autophagy is regulated by a collaborative interaction between tumor and immune cell components in distinct HCC microenvironments, thus allowing the inflammatory monocytes to be rerouted in a tumor-promoting direction.     

MiR-210-3p-EphrinA3-PI3K/AKT axis regulates the progression of oral cancer

This study aimed to explore new therapeutic targets to improve the survival rate of patients with oral squamous cell carcinoma (OSCC).MiR-210-3p, EphrinA3 and EMT related indices were evaluated in OSCC tissues and cell lines. In addition, the relationship between differential EphrinA3 expression and tumour progression was explored through molecular biology techniques, in vitro functional experiments and tumour xenotransplantation models. The expression of EphrinA3 (r_s = −0.719, P < .05) and E-cadherin (r_s = −0.856, P < .05) was negatively correlated with the pathological grading in OSCC tissues. Protein clustering shows EphrinA3 may be associated with tumour progression. EphrinA3 also can regulate the biological behaviour of oral cancer cells. And it regulates the EMT by the PI3K/AKT signalling pathway. MiR-210-3p targeted the gen EFNA3. Up-regulation of miR-210-3p expression can decrease the expression of EphrinA3 and further to influence the biological behaviour of OSCC. The miR-210-3p-EphrinA3-PI3K/AKT signalling axis plays an important role in the progress of OSCC. EphrinA3 may serve as a novel target for oral cancer treatment.     

On the proportion of cancer stem cells in a tumour

It is now generally accepted that cancers contain a sub-population, the cancer stem cells (CSCs), which initiate and drive a tumour’s growth. At least until recently it has been widely assumed that only a small proportion of the cells in a tumour are CSCs. Here we use a mathematical model, supported by experimental evidence, to show that such an assumption is unwarranted. We show that CSCs may comprise any possible proportion of the tumour, and that the higher the proportion the more aggressive the tumour is likely to be.     

Differentiation antigens of hemoblastoses and epithelial tumors: Relations to the mechanisms of transformation and progression

The role of mechanisms underlying differentiation is considered in malignant transformation of hemoblastoses and epithelial tumors. In hemoblastoses, differentiation is intimately related to malignant transformation and they are underlain by the same mechanisms. Immunophenotyping of hemoblastoses is fully based on successive stages of their differentiation with characteristic expression of differentiation antigens. Unlike hemoblastoses, epithelial tumors gradually, in the course of progression, lose their differentiation due to the degradation of the connections with the microenvironment, which controls the direction and level of epithelial differentiation. Therefore, carcinomas are characterized by varying degrees of “antigenic simplification”, including the epithelial-mesenchymal transition.     

The tumor microenvironment: An irreplaceable element of tumor budding and epithelial-mesenchymal transition-mediated cancer metastasis

Tumor budding occurs at the invasive front of cancer; the tumor cells involved have metastatic and stemness features, indicating a poor prognosis. Tumor budding is partly responsible for cancer metastasis, and its initiation is based on the epithelial-mesenchymal transition (EMT) process. The EMT process involves the conversion of epithelial cells into migratory and invasive cells, and is a profound event in tumorigenesis. The EMT, associated with the formation of cancer stem cells (CSCs) and resistance to therapy, results from a combination of gene mutation, epigenetic regulation, and microenvironmental control. Tumor budding can be taken to represent the EMT in vivo. The EMT process is under the influence of the tumor microenvironment as well as tumor cells themselves. Here, we demonstrate that the tumor microenvironment dominates EMT development and impacts cancer metastasis, as well as promotes CSC formation and mediates drug resistance. In this review, we mainly discuss components of the microenvironment, such as the extracellular matrix (ECM), inflammatory cytokines, metabolic products, and hypoxia, that are involved in and impact on the acquisition of tumor-cell motility and dissemination, the EMT, metastatic tumor-cell formation, tumor budding and CSCs, and cancer metastasis, including subsequent chemo-resistance. From our point of view, the tumor microenvironment now constitutes a promising target for cancer therapy.