Effect of tumor microenvironment-derived factors on melanoma cell growth and drug-response : an in vitro study in three-dimensional cultures.

Abstract

The incidence rate of malignant melanoma is increasing in Norwegian population as well as worldwide. It’s one of the most aggressive human cancers showing exceptional abilities to metastasize and develop resistance to therapy, and ccurrently there are no effective treatments against metastatic melanoma. Traditionally, melanoma aggressiveness was linked to intrinsic properties of the malignant cells themselves. However, it is becoming apparent now that the tumour microenvironment (TME) factors – non-malignant (stroma) cells, soluble molecules and extracellular matrix components – can play an important role in modulating metastatic properties and drug-sensitivity of cancer cells. In the present work we investigated how various TME factors like extracellular matrix components like fibronectin and laminin and soluble factors released from mice organs – common sites of melanoma metastasis - affected melanoma cells, specifically their metastasis-associated properties like growth/proliferation and sensitivity to the experimental dug Elesclomol. The study was based on three-dimensional (3D) in vitro cultures, where melanoma cells were grown in a Collagen or Matrigel matrix in the presence of investigated factors of TME. Two melanoma cells lines, Melmet 1 and Melmet 5 derived from the metastatic melanoma patents with different clinical indications were employed. It was observed that fibronectin and laminin did not have a notable effect on cell growth or viability. However, the soluble factors from the organs showed a slight stimulating effect on cell growth and a notable effect on cell morphology and growth pattern. The latter was especially pronounced for the bone marrow-derived factors. Comparison of the sensitivity of Melmet cells to Elesclomol in 3D versus 2D revealed, that 3D cultures were less sensitive to the drug, and that Melmet 5 was less sensitive compared to Melmet 1. The sensitivity was not modulated by the soluble factors derived from the healthy or metastatic brain.