Abstract
Resistance to chemotherapy is a principal problem in the treatment of small cell lung cancer (SCLC). We show here that SCLC is surrounded by an extensive stroma of extracellular matrix (ECM) at both primary and metastatic sites. Adhesion of SCLC cells to ECM enhances tumorigenicity and confers resistance to chemotherapeutic agents as a result of beta1 integrin-stimulated tyrosine kinase activation suppressing chemotherapy-induced apoptosis. SCLC may create a specialized microenvironment, and the survival of cells bound to ECM could explain the partial responses and local recurrence of SCLC often seen clinically after chemotherapy. Strategies based on blocking beta1 integrin-mediated survival signals may represent a new therapeutic approach to improve the response to chemotherapy in SCLC.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Chloromethyl Ketones / pharmacology
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Apoptosis / physiology*
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Bradykinin / pharmacology
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Carcinoma, Small Cell / drug therapy
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Carcinoma, Small Cell / metabolism*
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Carcinoma, Small Cell / pathology*
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Caspase 3
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Caspase Inhibitors
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Caspases / metabolism
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Cell Adhesion / drug effects
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Cell Division / physiology
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Collagen / metabolism
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Cyclophosphamide / pharmacology
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Doxorubicin / pharmacology
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Drug Resistance, Neoplasm
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Enzyme Inhibitors / pharmacology
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Etoposide / pharmacology
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Extracellular Matrix Proteins / metabolism*
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Fibronectins / metabolism
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Galanin / pharmacology
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Humans
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Integrin beta1 / metabolism
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Laminin / metabolism
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Lung Neoplasms / drug therapy
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Lung Neoplasms / metabolism*
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Lung Neoplasms / pathology*
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / metabolism
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Tenascin / metabolism
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Tumor Cells, Cultured
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Tyrphostins / pharmacology
Substances
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Amino Acid Chloromethyl Ketones
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Antineoplastic Agents
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Caspase Inhibitors
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Enzyme Inhibitors
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Extracellular Matrix Proteins
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Fibronectins
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Integrin beta1
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Laminin
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Tenascin
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Tyrphostins
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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tyrphostin 25
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Etoposide
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Doxorubicin
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Galanin
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Cyclophosphamide
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Collagen
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Protein-Tyrosine Kinases
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CASP3 protein, human
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Caspase 3
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Caspases
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Bradykinin