Abstract 5226: In vivo imaging and molecular characterization of site-specific growth of malignant melanoma: a study of melanoma metastasis in experimental animal models
Authors: Prasmickaite Lina , Nygaard Vigdis , Kristian Alexander , Høifødt Hanne Kleppe , Fodstad Øystein , Hovig Eivind , Mælandsmo Gunhild Mari 
Published: June 2012

Metastatic melanoma is a very aggressive and fatal disease in need of novel therapeutic targets. Melanomas are notorious for the ability to disseminate to almost any organ. The ability to develop metastases at distant sites is not only a function of intrinsic properties of the malignant cells themselves, but is also influenced by a wide range of factors in the host microenvironment. Understanding of the biological role of the microenvironment in the establishment of metastases and identifying implicated factors, might uncover novel potential targets for anti-metastatic therapy. The aim of our study was to reveal characteristics of metastatic growth of melanoma in different anatomical sites in animal models through in vivo imaging and molecular approaches.

We have developed experimental metastasis models in nude mice based on intracardial (left ventricle) injection of the melanoma cell lines Melmet 1 and Melmet 5, established from two metastatic melanoma patients with different clinical presentations. A follow-up of melanoma cell migration and micro/macrometastases formation assessed by molecular and functional imaging in vivo (IVIS and PET), indicated that Melmet 5 could establish metastases in multiple organs (including brain, lung, lymph nodes, kidney, bone), while Melmet 1 displayed a more consistent preference for the brain. Flow cytometric analysis of metastatic organs, specifically brain and lungs, revealed the recruitment of bone marrow derived cells, identified as CD11b+/Gr-1+ myeloid cells and CD11b+/F4/80+ macrophages. These cell subpopulations have been linked to the formation of a (pre)metastatic niche, and we are presently investigating their contribution to the metastatic growth of melanoma. Further, we performed a comparative microarray study to investigate differential gene expression with respect to organ-specific environments. Specifically, we identified a set of genes altered in immunoselected melanoma cells purified from brain tissue. Among these genes were receptors involved in glutamate signaling, indicating metabolic changes associated with metastatic colonization of the brain. Furthermore, after separation of tumor cells, the remaining host brain tissue was also analyzed by gene expression profiling in order to reveal molecular changes induced in the stroma compartment by metastases. Compared to non-diseased brain, we found altered expression of genes implicated in biological activities such as immune defense, evasion of apoptosis and cell adhesion and migration. Based on the results obtained, we are currently performing functional studies on candidate genes to elucidate their role in metastatic growth of melanoma. Targeting focal points of communication between metastatic tumor cells and the host in distinct microenvironments may represent an anti-metastatic therapeutic strategy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5226. doi:10.1158/1538-7445.AM2011-5226