Endocrine Abstracts

Small cell lung cancer (SCLC) is distinguished by its neuroendocrine phenotype and secretion of hormone biomarkers. Tumours initially respond well to therapy but almost invariably relapse with a therapy-resistant phenotype. We have previously described pro-opiomelanocortin (POMC) as a potential biomarker of SCLC. In this study, we investigated how POMC acts as a biomarker of tumour response to treatment.

SCLC cells (DMS 79) were injected subcutaneously into nude mice and tumours were irradiated for 3, 5 or 10 consecutive days at 2 Gy or left untreated. Circulating POMC strongly mimicked tumour growth in untreated animals. After irradiation, tumours decreased in size and subsequently grew back to the same size as untreated tumours. POMC concentrations mimicked tumour size. However, in those tumours receiving the high dose irradiation, circulating POMC, tumour POMC protein and gene expression were all significantly decreased. Other neuroendocrine markers including neuron specific enolase (NSE) and neural cell adhesion molecule (N-CAM) were unchanged.

To determine whether this change in biomarker expression was associated with irradiation-resistance occurring, DMS 79 cells were made resistant by repeated exposure in vitro. POMC expression was again significantly lower in the irradiation-resistant cells with NSE, N-CAM and chromogranin A expression unchanged. In addition, irradiation-resistant cells showed a drastically altered morphology, increased proliferation and an upregulation of genes associated with a more mesenchymal phenotype.

The changes to the neuroendocrine phenotype in response to irradiation are complex, as the decrease in POMC in vivo and in vitro occurred in the absence of changes in other neuroendocrine markers. This indicates that extensive characterisation of biomarkers is necessary to understand their plasticity and the implications for their use. The transition to a more mesenchymal phenotype after irradiation suggests that despite the obvious advantage of treating SCLC with radiotherapy, the remaining cells may have a greater propensity to metastasise.

The changes to the neuroendocrine phenotype in response to irradiation are complex, as the decrease in POMC in vivo and in vitro occurred in the absence of changes in other neuroendocrine markers. This indicates that extensive characterisation of biomarkers is necessary to understand their plasticity and the implications for their use. The transition to a more mesenchymal phenotype after irradiation suggests that despite the obvious advantage of treating SCLC with radiotherapy, the remaining cells may have a greater propensity to metastasise.