Editors' ChoiceTUMOR MICROENVIRONMENT

Creating Refuge

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Science Translational Medicine  09 Oct 2013:
Vol. 5, Issue 206, pp. 206ec167
DOI: 10.1126/scitranslmed.3007714

The long-held view that therapeutic resistance evolves purely from selection of insensitive tumor cells has been challenged with increasing frequency by studies that demonstrate a role for the microenvironment in conveying resistance to chemotherapeutics or radiotherapy. Microenvironmental constituents, such as extracellular matrix (ECM) proteins laminin-111, fibronectin, and collagen VI, have been shown to convey resistance to apoptosis in response to chemotherapeutics, targeted therapies, or radiotherapy, primarily by binding their cognate receptors on cell surfaces (integrins) and hyperactivating cell survival pathways. In most cases, it was demonstrated or assumed that surviving cells either existed in privileged niches or sought refuge within niches rich in said ECM components in order to survive.

A recent study offers a third possibility, namely, that inhibition of the epidermal growth factor receptor (EGFR) directly stimulates fibronectin production, effectively allowing tumor cells to create their own chemoresistant niche. To test this hypothesis, the authors used a combination of cell culture studies with non–small cell lung cancer (NSCLC) cell lines and xenograft models in mice and showed that direct inhibition of EGFR function with the monoclonal antibody therapeutic cetuximab or small interfering RNA–mediated knockdown of EGFR expression resulted in an up-regulation in fibronectin synthesis by NSCLC cells. The NSCLC cells that bound to fibronectin (via the α5β1 integrin) were resistant to cetuximab treatment or radiation regimens. By using antibody arrays, the authors identified the mitogen-activated protein kinase family member p38, acting through the ATF2 transcription factor, as a prime mediator of enhanced fibronectin production in NSCLC cells subjected to cetuximab treatment.

Many therapeutics that have displayed subpar clinical success, such as cetuximab, performed lavishly in preclinical studies, often because these studies failed to take into account robust survival signals provided by the tumor microenvironment. Ironically, improving the efficacy of these therapies may require that we devise strategies to effectively render tumor cells an island once again. The study by Eke et al. provides a number of molecules to target in order to block NSCLC cell creation of a fibronectin-rich refuge. Whether inhibition of α5β1 integrin, p38, or activating transcription factor 2 will render NSCLC cells more susceptible to cetuximab or radiotherapy in the clinic remains to be seen.

I. Eke et al., Cetuximab attenuates its cytotoxic and radiosensitizing potential by inducing fibronectin biosynthesis. Cancer Res. 73, 5869 (2013). [Abstract]

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