Medicine in focus
Small cell lung cancer: the importance of the extracellular matrix

https://doi.org/10.1016/S1357-2725(03)00261-9Get rights and content

Abstract

Lung cancer is the leading cause of cancer deaths in the UK and the small cell lung cancer (SCLC) phenotype is the most aggressive form of this disease, with a high metastatic potential and the development of resistance to chemotherapy. Evidence now suggests that these features may be due to important links between the cancer cells and proteins in their local extracellular matrix (ECM). This article reviews the evidence for a chemoprotective effect of extracellular matrix in small cell lung cancer and discusses the importance of integrin-mediated signalling pathways in this setting.

Introduction

Carcinoma of the lung is the leading cause of cancer deaths in UK and Wales and the third most common cause of all deaths. Small cell lung cancer (SCLC) accounts for around 20% of all cases but has the poorest prognosis—untreated, median survival from diagnosis is in the range of 5–12 weeks, but even with therapy median survival is only in the region of 8 months and 2 year survival is less than 5% (Osterlind, Hansen, Hansen, Dombernowsky, & Andersen, 1986). Of all lung cancers, SCLC has the strongest association with smoking (Wu, Henderson, Thomas, & Mack, 1986). Smoking cessation should therefore remain a prime goal in long-term healthcare planning, but with continued high levels of smoking amongst younger generations and a burgeoning population of smokers in developing countries (Liu et al., 1998) lung cancer will remain a major healthcare burden for the foreseeable future. Research must be directed at understanding the cellular and molecular biology of this disease so that rational and effective therapies may be developed.

SCLC has the highest degree of metastasis of all solid tumours, with 80–90% of patients suffering local or distant metastases at presentation, precluding the possibility of curative surgery. Further, although SCLC is initially highly sensitive to chemotherapy and radiotherapy, with radiological resolution in 50–80% of cases, the disease invariably relapses, with the development of increasing resistance to all modalities of treatment 1. Evidence suggests that these cardinal features of a high metastatic potential and the development of chemoresistance, which are the principal causes of poor survival, are the result of complex interactions between SCLC cells and extracellular matrix (ECM) in their local environment. This article will review recent work by our group and others that has elucidated some of the molecular mechanisms involved in such interactions, focussing specifically on the role of integrins in mediating chemoresistance.

Section snippets

Background

Integrins are cell adhesion receptors that allow a cell to interact with ECM in the local environment. They are heterodimeric transmembrane proteins composed of α and β subunits and more than 20 have been identified (Hynes, 1992), many of which demonstrate specific binding to components of the extracellular matrix such as laminin, fibronectin or collagen. The affinity with which integrins bind to ligands is highly dynamically regulated, between low affinity (suppressed) and high affinity

Extracellular matrix protects against chemotherapy in SCLC

Despite initial sensitivity to chemotherapy, partial responses and local recurrence are commonly seen with subsequent resistance to chemotherapy, suggesting that components of the local microenvironment may protect SCLC from the cytotoxic effects of chemotherapy. An immunohistochemical study of 23 resected SCLC samples revealed high levels of fibronectin, collagen IV and tenascin in all samples (Sethi et al., 1999). This high expression was localized to the reactive, desmoplastic stroma around

The mechanism underlying ECM-mediated protection

Chemotherapeutic agents such as adriamycin and etoposide induce apoptosis by inhibiting the nuclear enzyme DNA topoisomerase II, normally responsible for relaxation of supercoiled DNA by inducing transient double strand breaks (Smith et al., 1994). These agents permit the accumulation of DNA strand breaks, leading to programmed cell death via the final common pathway in which caspase-3 (formed from pro-caspase-3) cleaves the chaperone inhibitor of caspase-activated deoxyribonuclease, triggering

Supportive data

This phenomenon of ECM-mediated chemoresistance appears to have general application in cancers. An earlier report by Fridman et al. (1990) showed that matrigel and laminin were able to enhance SCLC tumourigenicity and drug resistance in SCLC. In xenograft-derived endothelial cells, culture on gelatin, collagen IV, laminin, fibronectin or the integrin ligand peptide Gly–Arg–Gly–Asp–Ser–Pro (but not the integrin peptide Gly–Arg–Ala–Asp–Ser–Pro) prevented etoposide-induced DNA damage (Hoyt et al.,

Paradoxes with clinical reality

Alongside this accumulating evidence for a cytoprotective effect of the ECM, it has been noted for some time that one of the features of malignant tumours was expression of matrix metalloproteinases (MMPs), a family of proteolytic enzymes that may facilitate tumour invasion, metastasis and angiogenesis (reviewed in Bonomi, 2002). MMP inhibitors (MMPIs) have now been shown to have efficacy in reducing tumour growth, blood vessel density and metastasis in a number of in vivo animal models of

Concluding remarks

Small cell lung cancer remains a condition with an appalling clinical outlook, due to its high metastatic potential and the development of chemoresistance. We have discussed how these features may be fundamentally influenced by a dynamic relationship existing between the cancer cells and their surrounding ECM. In particular, we have reviewed the increasing evidence, supported in other cell types, of an integrin-mediated signalling pathway conferring protection against chemotherapy-induced

Acknowledgements

R.C.B. and R.C.R. were supported by Medical Research Council Training Fellowships. T.S. is supported by a Wellcome Trust Senior Leave Research Fellowship.

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