Immune Suppression and Colorectal Cancer

C. Evans; A. G. Dalgleish; D. Kumar

Disclosures

Aliment Pharmacol Ther. 2006;24(8):1163-1177. 

In This Article

Escaping Death Receptors

Death ligands, Fas ligand (FasL) and TNF-related apoptosis-inducing ligand (TRAIL) engage with cell surface death receptors, Fas and TRAIL-R1/-R2, respectively, and are involved in immune-mediated neutralization of tumour cells.[129] Tumour cells can become resistant to death receptor-induced apoptosis through a number of complex mechanisms and at several levels of signal transduction.[130]

Colorectal tumours have the potential to escape Fas-mediated apoptosis by losing cell surface Fas expression.[131] Inhibition of signal transduction can occur as a result of the expression of a number of different molecules by the tumour cells, such as Fas-associated phosphatase-1 (FAP-1),[132] FLICE-like inhibitory protein (cFLIP)[133] and AMP-activated protein kinase-related kinase 5 (ARK5).[134] TRAIL has exceptional antitumour potential because of its high cell specificity in terms of induction of apoptosis and its ability to induce tumour regression without causing toxicity to other cells.[135] However, not all human colon cancer cell lines are sensitive to TRAIL because of an intrinsic or acquired resistance.[136] Sensitivity to TRAIL-induced apoptosis correlates with the cell surface expression of death receptors TRAIL-R1 and TRAIL-R2[137] and the presence of cell surface decoy receptor proteins TRID and TRUNDD which have been demonstrated on colon cancer cells.[138] Upon TRAIL receptor ligation an apoptotic signal is transmitted triggering a cascade of capases involving caspase 8 (FLICE), capases 3, 6 and 7. Expression of the FLICE inhibitory protein (FLIP) allows tumour cells to become resistant to this death receptor signalling[16] and is expressed in colorectal tumours.[139] Further downstream in the TRAIL apoptotic pathway, Bax mutations, or increased expression of IAP family members, especially XIAP and survivin, also cause resistance.[136]

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