The success of anticancer therapy is usually limited by the development of drug resistance. Such acquired resistance is driven, in part, by intratumoural heterogeneity - that is, the phenotypic diversity of cancer cells co-inhabiting a single tumour mass. The introduction of the cancer stem cell (CSC) concept, which posits the presence of minor subpopulations of CSCs that are uniquely capable of seeding new tumours, has provided a framework for understanding one dimension of intratumoural heterogeneity. This concept, taken together with the identification of the epithelial-to-mesenchymal transition (EMT) programme as a critical regulator of the CSC phenotype, offers an opportunity to investigate the nature of intratumoural heterogeneity and a possible mechanistic basis for anticancer drug resistance. In fact, accumulating evidence indicates that conventional therapies often fail to eradicate carcinoma cells that have entered the CSC state via activation of the EMT programme, thereby permitting CSC-mediated clinical relapse. In this Review, we summarize our current understanding of the link between the EMT programme and the CSC state, and also discuss how this knowledge can contribute to improvements in clinical practice.

EMT, CSCs, and drug resistance: the mechanistic link and clinical implications

The identification of genes predisposing to familial cancer is an essential step towards understanding the molecular events underlying tumorigenesis and is critical for the clinical management of affected families. Despite a declining incidence, gastric cancer remains a major cause of cancer death worldwide, and about 10% of cases show familial clustering. The relative contributions of inherited susceptibility and environmental effects to familial gastric cancer are poorly understood because little is known of the genetic events that predispose to gastric cancer. Here we describe the identification of the gene responsible for early-onset, histologically poorly differentiated, high grade, diffuse gastric cancer in a large kindred from New Zealand (Aotearoa). Genetic linkage analysis demonstrated significant linkage to markers flanking the gene for the calcium-dependent cell-adhesion protein E-cadherin. Sequencing of the E-cadherin gene revealed a G --> T nucleotide substitution in the donor splice consensus sequence of exon 7, leading to a truncated gene product. Diminished E-cadherin expression is associated with aggressive, poorly differentiated carcinomas. Underexpression of E-cadherin is a prognostic marker of poor clinical outcome in many tumour types, and restored expression of E-cadherin in tumour models can suppress the invasiveness of epithelial tumour cells. The role of E-cadherin in gastric cancer susceptibility was confirmed by identifying inactivating mutations in other gastric cancer families. In one family, a frameshift mutation was identified in exon 15, and in a second family a premature stop codon interrupted exon 13. These results describe, to our knowledge for the first time, a molecular basis for familial gastric cancer, and confirm the important role of E-cadherin mutations in cancer.

E-cadherin germline mutations in familial gastric cancer

Phenolics in Food and Nutraceuticals is the first single-source compendium of essential information concerning food phenolics. This unique book reports the classification and nomenclature of phenolics, their occurrence in food and nutraceuticals, chemistry and applications, and nutritional and health effects. In addition, it describes antioxidant activity of phenolics in food and nutraceuticals as well as methods for analysis and quantification. Each chapter concludes with an extensive bibliography for further reading. Food scientists, nutritionists, chemists, biochemists, and health professionals will find this book valuable.

Phenolics in food and nutraceuticals

http://www.heavythinking.org/cp-blog/wp-content/uploads/2011/03/Flemming-et-al-1999-Effects-of-synthetic-micro-and-nano-structured-surfaces-on-cell-behaviour.pdf

Effects of synthetic micro- and nano-structured surfaces on cell behavior

https://www.cell.com/molecular-cell/pdf/S1097-2765(01)00260-X.pdf

The Two-Handed E Box Binding Zinc Finger Protein SIP1 Downregulates E-Cadherin and Induces Invasion

Cancer cells are genetically predisposed to contribute to the formation of a malignant tumor. As a population they do not respect tissue boundaries, but penetrate into the surrounding normal tissues. On their way to lymph or blood vessels they create a path of destruction. This invasive behavior eventually gives access to the circulation, and opens a gate to metastatic dissemination(Nicolson et al.; Fidler and Hart 1982; Mareel et al. 1993).

The E-cadherin/catenin complex in invasion and metastasis.

Metastasis determines cancer malignancy. Neoplastic cells metastasize through a multistep process of invasion. At each step, these cells create a dynamic micro-ecosystem in which the elements of the host are considered to paricipate actively invasion. Within such micro-ecosystems, invasion is believed to be governed by a balance between the activation of promoter (i-minus) and suppressor (i-plus) genes. Products of such genes regulate the expression of the invasive (I-plus) and the nonivasive (I-minus) phenotypes. Experimentsin vitro andin vivo, as well as observations on human cancers have put forward the cell-cell adhesion molecule E-cadherin (L-CAM; uvomorulin) as a regulator of epithelial organization and an invasion suppressor.

Invasion promoter versus invasion suppressor molecules: the paradigm of E-cadherin

The acquisition of invasiveness is a crucial step in the malignant progression of cancer. In cancers of the colon and of other organs the E-cadherin/catenin complex, which is implicated in homotypic cell-cell adhesion as well as in signal transduction, serves as a powerful inhibitor of invasion. We show here that one allele of the alphaE-catenin (CTNNA1) gene is mutated in the human colon cancer cell family HCT-8, which is identical to HCT-15, DLD-1 and HRT-18. Genetic instability, due to mutations in the HMSH6 (also called GTBP) mismatch repair gene, results in the spontaneous occurrence of invasive variants, all carrying either a mutation or exon skipping in the second alphaE-catenin allele. The alphaE-catenin gene is therefore, an invasion-suppressor gene in accordance with the two-hit model of Knudsen for tumour-suppressor genes.

The αE-catenin gene (CTNNA1) acts as an invasion-suppressor gene in human colon cancer cells

Catechins, a group of flavonoid molecules, inhibit invasion of mouse MO4 cells into embryonic chick heart fragments in vitro. The anti-invasive effects can be ranked as follows: (+)-catechin greater than (-)-epicatechin greater than 3-O-methyl-(+)-catechin greater than 3-O-palmitoyl-(+)-catechin. Most of the catechins are unstable in cell culture media, and their spontaneous rearrangement products tend to bind to extracellular matrix (ECM). Due to these interactions proteases such as tissue-type plasminogen activator (t-PA) are linked to the ECM glycoprotein laminin. This leads to a partial inactivation of the enzyme. Within the group of catechins we found a positive correlation between anti-invasive activity and linking of t-PA to laminin. Citrus flavonoids are also anti-invasive in vitro (tangeretin greater than nobiletin greater than hesperidin = naringin). However, these stable molecules show poor affinity for ECM, and do not link enzymes to laminin. These data suggest that catechins and citrus flavonoids inhibit invasion in vitro by different mechanisms.

Effect of catechins and citrus flavonoids on invasion in vitro.

Citrus flavonoid effect on tumor invasion and metastasis

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