Development of cancer in vivo is determined by a variety of factors that cannot be duplicated in an in vitro short-term testing system because: (a) The concentration of ultimate reactive metabolites available to react in organs in animal species with cellular macromolecules, which is a consequence of a balance between metabolic activation and detoxication processes, is only partly reflected by in vitro testing procedures.
The Task Group on Metal Accumulation (1973) and the Task Group on Metal Toxicity (1976) have defined the critical concentration for a cell as the concentration (of a metal) at which undesirable (adverse) functional changes, reversible or irreversible, occur in the cell.
cell polarity and cancer essays in biochemistry ..
Thus, two quite different disease processes can have one common level of consideration, namely, their ability to produce alterations in the genetic material of cells.
Epithelial cell polarity: what flies can teach us about cancer
More recently it has been shown that cell competition could also play an opposite role during cancer formation. In fact there are now observations suggesting that surrounding normal cells can suppress the proliferation of tumour cells. Cells mutated in the tumour suppressors scrib and lgl are eliminated by wild-type cells, indicating that cell competition could act as a tumour suppressor mechanism eliminating potentially harmful cells from the tissue [–].
Epithelial cells are polarized along their apical–basal axis
CRB3 is an essential determinant of epithelial apical identity in epithelia. CRB3 maintains apical-basal polarity by ensuring the delivery and stabilization of junctional proteins and interacting with other polarity proteins such as ZO1 and PAR6. CRB3 is mainly deposited in the plasma membrane; therefore, it may mediate the extracellular signal transduction in cancer development via intracellular signal, such as Hippo signal. However, little is known about its mechanisms. Currently, most CRB studies are done on Drosophila. Drosophila crb greatly differs in the structure from mammalian CRB3; therefore, studies on mammalian CRB3 are needed. Based on the above review, new questions arise: Does CRB3 inhibit the Hippo signal by directly affecting Willin? Does CRB3 regulate activation of the Notch and other signals and how? In-depth research is needed to reveal the role of CRB3 in tumorigenesis.
Cell polarity and asymmetric cell division ..
The Notch signaling is involved in regulating many processes (proliferation, differentiation, cell death, and cell fate) during development and renewal of adult tissues . The Notch signaling mediates TGF-β-induced EMT through the induction of Snail . The Notch function changes during the development of cell differentiation and can be either oncogenic or tumour-suppressive, depending on cellular context . Crb has been shown to prevent endocytosis of the Notch receptor and/or its ligand Delta in Drosophila and zebrafish by directly interacting with these proteins via its lager extracellular structure; this may also negatively affect the epithelial tissue growth , , . However, overexpression of human CRB3 does not have this effect on Notch signaling in mammalian cells . Drosophila crb and human CRB3 have different roles in the Notch signaling because crb interacts with the Notch signaling mainly via the extracellular section of crb, whereas the extracellular CRB3 contains only signal peptide.
Cell Polarity and Cancer : Andrew D. Chalmers : …
The molecular mechanism by which CRB3 exerts its cancer suppressive function may be related to its interaction with the Hippo signaling , , . The Hippo signaling is a critical regulator of cell cycle, proliferation, apoptosis, differentiation and contact inhibition . CRB3 regulates proliferation and apoptosis via mediation of the Hippo signaling. Crb suppresses cancer development in Drosophila by regulating the Hippo signaling via the FERM-domain protein Expanded , , . However, the mechanism underlying the interaction between CRB3 and Hippo signaling in human is unclear. It has been suggested that FRMD6/Willin is a homologue of Expanded , and it also has an FERM domain. Whether CRB3 regulates the Hippo signaling in human needs to be further verified . FRMD6/Willin may be regulated by CRB3 and forms a complex with KIBRA and MER. The complex ultimately phosphorylates the transcription co-activator Yes-associated protein (YAP)/the transcriptional co-activator with PDZ-binding domain (TAZ, also known as WWTR1). The phosphorylated YAP/TAZ binds to the 14-3-3 protein and is retained in cytoplasm. Cytoplasmic YAP/TAZ suppresses TGF-β signaling, which in turn prevents the nuclear accumulation of the SMAD complex and inhibits the Wnt/β-catenin signaling -. Inhibition of the Wnt/β-catenin signaling downregulates TJ markers ZO1 and E-cadherin, induces EMT , and ultimately triggers cancer metastasis , , .