LONDON ¿ Small-cell lung cancer is a very aggressive cancer. In 95 percent of cases, by the time the patient realizes that he or she is ill, it has spread widely. The good news is that the tumor appears to respond well to chemotherapy. The bad news is that the tumor¿s sensitivity to the drugs does not last.

Commonly, the tumor recurs at the same site, and the patient will be dead within months.

Such observations prompted a group of researchers in Edinburgh, Scotland, to examine the local environment of small-cell lung cancer to find out if anything was preventing the tumor from being completely killed off by chemotherapy, or if the tumor cells were somehow protected from chemotherapy-induced death.

Tariq Sethi, senior lecturer and honorary consultant in the department of respiratory medicine at the University of Edinburgh, told BioWorld International, ¿Our findings suggest that it may be possible to develop new strategies that would be able to improve the response to chemotherapy, and thus kill all the cells in this type of cancer.¿

Sethi, together with collaborators in Edinburgh and at the University of Michigan Medical Center in Ann Arbor, report their findings in the June issue of Nature Medicine, in a paper titled ¿Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: A mechanism for small cell lung cancer growth and drug resistance in vivo.¿

The study examines the role of cell adhesion in tumor cell biology. Normally, epithelial and endothelial cells need to stick to an extracellular stroma of proteins known as the extracellular matrix proteins ¿ a phenomenon called ¿anchorage dependence.¿ If the cells come loose, this triggers their entry into the pathway leading to programmed cell death, or apoptosis.

Apoptosis is avoided when proteins on the surface of the cell, called integrin receptors, bind to the extracellular matrix proteins. This down-regulates production of an enzyme which plays an important role in apoptosis. Cancer cells are noted, however, for their ¿anchorage independence,¿ which allows them to grow without sticking to the extracellular matrix proteins.

Sethi and colleagues obtained biopsy samples of small-cell lung cancer and examined the environment in which the tumors were growing. They found that both primary tumors and secondary tumors were surrounded by an extensive stroma of extracellular matrix proteins. In subsequent experiments, they found that when integrin receptors on the cells bound to the extracellular matrix proteins, this triggered a signal inside the cell, aborting its entry into chemotherapy-induced apoptosis.

Sethi told BioWorld International, ¿These results suggest that despite chemotherapy-induced DNA damage within the cell ¿ which would normally cause apoptosis ¿ signaling induced by adhesion drives the cells to carry on dividing. As a result of adhesion, integrin receptors undergo some conformational change which then signals into the cell, and this signaling is what protects the cells against apoptosis. After this, cells are selected which are resistant to further chemotherapy.¿ The team also shows that the signal to avoid apoptosis is mediated via enzymes called tyrosine kinases.

The next phase of the project will involve finding out exactly which enzymes are involved, and how they work, with a view to developing ways of inhibiting them. ¿Our hypothesis is that it may be possible to develop strategies based on blocking integrin-mediated survival signals, in which case we could improve the response to chemotherapy,¿ Sethi said. ¿One problem is that all cells use beta 1 integrins, so blocking this molecule would probably be very toxic. But, if we could find specific pathways that lung cancers are using ¿ and there are signs that we may be able to ¿ we could perhaps block these with pharmacological agents which could be given as adjuvant therapies with existing chemotherapeutic agents.¿