Review
Transcriptional control of melanoma metastasis: The importance of the tumor microenvironment

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Abstract

The molecular changes associated with the transition of melanoma cells from radial growth phase (RGP) to vertical growth phase (VGP) and the metastatic phenotype are not very well defined. However, some of the genes involved in this process and their transcriptional regulation are beginning to be elucidated. For example, the switch from RGP to VGP and the metastatic phenotype is associated with loss of the AP-2α transcription factor. AP-2α regulates the expression of c-KIT, MMP-2, VEGF, and the adhesion molecule MCAM/MUC18. Recently, we reported that AP-2α also regulates two G-protein coupled receptors (GPCRs) PAR-1 and PAFR. In turn, the thrombin receptor, PAR-1, regulates the expression of the gap junction protein Connexin-43 and the tumor suppressor gene Maspin. Activation of PAR-1 also leads to overexpression and secretion of proangiogenic factors such as IL-8, uPA, VEGF, PDGF, as well certain integrins. PAR-1 also cooperates with PAFR to regulate the expression of the MCAM/MUC18 via phosphorylation of CREB. The ligands for these GPCRs, thrombin and PAF, are secreted by stromal cells, emphasizing the importance of the tumor microenvironment in melanoma metastasis. The metastatic phenotype of melanoma is also associated with overexpression and function of CREB/ATF-1. Loss of AP-2α and overexpression of CREB/ATF-1 results in the overexpression of MCAM/MUC18 which by itself contributes to melanoma metastasis by regulating the inhibitor of DNA binding-1 (Id-1). CREB/ATF-1 also regulates the angiogenic factor CYR-61. Our recent data indicate that CREB/ATF-1 regulates the expression of AP-2α, thus, supporting the notion that CREB is an important “master switch” in melanoma progression.

Introduction

Melanoma progresses through a number of sequential events which must occur for establishment of metastatic lesions. Through genetic alterations, normal melanocytes are transformed into a benign nevus. Further molecular alterations lead to a premalignant lesions which grow and spread through the epidermis in a premalignant radial growth phase (RGP). The expression of basement membrane and matrix-degrading enzymes lead to local invasion through the dermis termed vertical growth phase (VGP), which allows for tumor cells to enter into the lymphatic and vascular networks [1], [2]. The tumor cells must have the acquired ability to survive the circulation, arrest in the capillary bed of the distant organ, enter the parenchyma, grow within the organ microenvironment, and further initiate angiogenesis [1]. Only a small subset of cells from the primary tumor have the acquired molecular changes to complete the metastatic cascade and grow in select organs such as the lymph nodes, lung, liver, and brain [3]. Patient survival depends greatly on identifying the disease before the later events of the cascade can occur. Patients presenting with stage I and II disease, with no observable metastasis, have a five-year survival rate of approximately ninety and seventy percent respectively. Patients with lymph node involvement, stage III, have approximately a forty-five percent five-year survival; however, prognosis can worsen if metastasis has occurred in multiple lymph nodes. Once metastasis to distant organs occurs, the five-year survival rate significantly decreases to ten percent [4].

Melanoma has become an ideal model for identifying the molecular changes that occur during the metastatic transition. Multiple events have been identified during these well characterized sequential events from melanocyte to benign nevus, to the radial growth phase (RGP), then to the vertical growth phase (VGP), and finally metastasis [5]. The molecular changes occurring at specific stages of melanoma can infer that certain molecules are critical for the disease to initiate tumor development, angiogenesis, and survival. Others are required for the degradation of matrix membranes and entrance into the circulation. Finally, transcriptional regulation of certain molecules is required for transportation, extravasation, and homing to distant organs [1]. The deregulation of transcription factors during the transition form RGP to VGP, along with their downstream target genes can regulate the metastatic phenotype of melanoma. This review will summarize our data on the roles of two transcription factors, AP-2α and CREB/ATF1 as major players determining the malignant melanoma phenotype.

Section snippets

Loss of the transcription factor AP-2α expression enhances the metastatic melanoma phenotype

The acquisition of the metastatic melanoma phenotype can occur through the overexpression or repression of genes through transcription activators or repressors. The transcription factor AP-2α is a 52 kDa protein first purified from HeLa cells [6]. The gene can be alternatively spliced to form the dominant-negative AP-2B protein that differs in its C-terminus, which inhibits AP-2α transcriptional activity [7]. Immunohistochemistry analysis of melanoma patients identified that the loss of AP-2α

Protease activated receptor-1 (PAR-1)

Melanoma utilizes the coagulation/platelet activation pathways by producing and responding to thrombin, tissue factor, fibrinogen, and platelet activating factor (PAF) [27], [28], [29], [30]. Thrombin activates platelets which leads to the release of angiogenic factors such as VEGF, angiopoietin-1, PDGF, and lysophosphatidic acid [31], [32], [33]. Cleavage of the N-terminal domain of PAR-1 by thrombin reveals a new N-terminal which acts as a tethered ligand and binds to the body of the

Adhesion molecules

Cell adhesion molecules play critical roles in normal biological functions such as membrane integrity and leukocyte tethering [63], [64]. They are cell surface molecules which can form homophilic or hetorophilic interactions with surrounding cells. In the case of melanoma and other cancers, these interactions allow for the aggregation of cancer cells to each other (homotypic adhesion) or to the host stroma and cells within the circulatory system (heterotypic adhesion) [65]. These interactions

Activation of CREB acts as a “major regulator” of metastatic melanoma

Several growth factors that increase melanocyte proliferation and differentiation can also upregulate cAMP [84], [85]. This has led to the investigation of cAMP-responsive element binding (CREB) protein and its role in melanoma. CREB is a member of the bZIP superfamily, and binds to the cAMP-responsive elements (CRE's) located on the promoter sequences of various genes. Phosphorylation at Ser133 of CREB leads to its activation and association with its co-activators CBP and p300 [86], [87]. CREB

Conclusion

Recent work has elucidated the relationship between AP-2α and CREB along with the molecular changes regulated by these two transcription factors during melanoma progression. The change in CREB and AP-2α activities leads to the downregulation of c-KIT, and overexpression of MMP-2, MCAM/MUC18, and two G-protein coupled receptors, PAR-1 and PAFR. Further signaling through these molecules enhances the expression of invasive, angiogenic, and survival factors, thus emphasizing the roles of the tumor

Conflict of interest

There is no conflict of interest.

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