Extracellular matrix regulation of drug resistance in small-cell lung cancer.
OBJECTIVE
Lung cancer is the leading cause of cancer deaths in the developed world. Small cell lung cancer (SCLC) has the worst prognosis due to the emergence of resistance to chemotherapy. This article will review recent work that has defined mechanisms of chemo-resistance focusing on the role of integrins.


RESULTS
SCLC is surrounded by an extensive stroma of extracellular matrix (ECM) and high levels of expression correlate with poor prognosis. ECM protects SCLC cells against chemotherapy-induced cell death by activating beta1 integrins leading to activation of phosphoinositide-3-OH kinase (PI3-kinase), which prevents etoposide-induced caspase-3 activation and subsequent apoptosis. Engagement of ECM prevents etoposide and radiation induced G2/M cell cycle arrest in SCLC cells by blocking the up-regulation of p21Cip1/WAF1 and p27Kip1 and the down-regulation of cyclins E, A and B. These effects are abrogated by pharmacological and genetic inhibition of PI3-kinase signalling.


CONCLUSIONS
Thus, ECM via beta1 integrin-mediated PI3-kinase activation allows SCLC cells to survive treatment induced cell cycle arrest and apoptosis with persistent DNA damage, providing a model to account for the emergence of acquired drug resistance. Novel therapeutic strategies may therefore be directed at inhibiting integrin-mediated cell survival signals improving response rates and cure in this devastating cancer.
Hodkinson
P S
PS
Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
Mackinnon
A C
AC
Sethi
T
T
D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology / Q000532:radiotherapy; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005109:Extracellular Matrix / Q000502:physiology*; D006801:Humans; D016023:Integrins / Q000502:physiology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology / Q000532:radiotherapy; D008954:Models, Biological; D011379:Prognosis; D015398:Signal Transduction
D016023:Integrins