Chemokine Receptors in Malignant Melanoma

Tumor growth, invasion and metastasis to distant organs are dependent on a highly orchestrated series of events. These events include cellular transformation , establishment of a pro-angiogenic environment, local tumor cell growth, invasion through the extracellular matrix and vascular basement membrane and entry into the circulation. Finally, extravasation of tumor cells at distant organs may occur in a nonrandom fashion. These events of tumor cell growth, progression and metastasis are analogous to leukocyte maturation, with subsequent entry into the circulation and eventual homing to specific tissue sites. For certain populations of leukocytes, migration and homing is accomplished by a specific group of cytokines, the chemokines. Chemokines are small, chemotactic cytokines that direct migration through binding to chemokine receptors. Chemokines are secreted by tumor cells and their receptors are expressed to modulate tumor behavior by three mechanisms, which are important for tumor development: regulation of tumor-associated angiogenesis, activation of a host tumor-specific immunological response, and direct stimulation of tumor cell proliferation in an autocrine fashion. In malignant melanoma, the most aggressive malignancy of cutaneous origin with a dramatic increase in incidence among white people, chemokines may be of paramount importance for tumor growth, progression and homing. Chemokines, like interleukin-8 (IL-8) and melanoma growth-stimulatory activity/growth - regulated genes are expressed in melanoma lesions and are likely to sustain autocrine or paracrine loops, which positively affect cell growth directly or through stimulation of angiognesis. As for chemokines, chemokine receptors, like CXCR1 and CXCR2, may be crucial for cellular transformation, leading to melanoma development. Based on our results of IL-8 promoted tumor growth and progression in melanoma cell lines from different stages, we intend to study the functional role of the IL-8 receptors CXCR1 and CXCR2 for the pathogenesis of melanoma by selectively targeting the receptors with specific antagonists. By means of an adenoviral based expression system we can modulate the expression of IL-8 as well as its antagonists resulting in a chemokine gradient, which directs the biological response towards a different phenotype. Interference with CXCR1 and CXCR2 will delineate the functional relevance of these receptors for melanoma development and are promising points of cancer intervention.

Malignant melanoma is the most aggressive skin tumor and incurable at advanced stage. Chemokines, chemotactic cytokines, and their receptors are responsible for site-directed migration of inflammatory cells. As with inflammatory cells, tumor cells secrete chemokines and express chemokine receptors, which are likely to be important for site-specific metastases. Because chemokines exert some more effects on tumors, like promoting growth or angiogenesis, they may be interesting targets for therapeutic interventions. Detailed information about the contribution of chemokine receptors and their ligands to growth and metastases in malignant melanoma are pending. This project aimed to characterise (i) chemokine receptor expression profiles in melanocytic lesions and (ii) to investigate on the tumor growth inhibiting properties of a viral chemokine receptor homologue. i) Chemokine receptors were found to be expressed in benign congenital nevi and melanoma tissue alike, but showed huge differences in expression levels. Two chemokine receptors were only expressed in melanoma tissue and not in congenital nevi. One of these, CXCR6, was increasingly expressed in melanoma metastases. This is of particular interest, since the occurrence of this receptor in melanoma has not been reported before. Therefore we intend to perform more in depth investigations in a new application. ii) Viral chemokine receptor homologues and chemokine binding proteins can scavenge multiple chemokines form the cell microenvironment. Scavenging of chemokines may be important for tumor growth, since it has been shown that tumor cells depend on proper secretion of chemokines. In an effort to investigate on the presumably tumor growth inhibiting properties of a viral chemokine receptor, we transduced melanoma cells with different constructs. In vitro we could demonstrate that a mutant of this viral receptor inhibits proliferation and in vivo tumor growth was abrogated or diminished, depending on the respective melanoma cell line. We will now perform more in depth investigations to gain data about the mechanisms, with regard to inhibition of proliferation and tumor growth. Additionally, effects on differentiated cells, like keratinocytes, fibroblasts and endothelial cells will be determined.