The development of tumor metastasis is a complex cascade of events [
1]. Potentially, metastatic cells have to exit the primary tumor site by loosening cell to cell contact, adhering to and degrading extracellular matrix (ECM), migrating through the subendothelial basement membrane of local post-capillary veins and lymphatic vessels and intravasating. Once in circulation, tumor cells face severe mechanical and immunosurveillance challenges. Surviving cells can arrest in the peripheral capillary bed of a distant organ, adhere to the subendothelial basement membrane, extravasate, adhere and migrate through the ECM, and form a colony at the new metastatic site. Further induction of neoangiogenesis must occur to assure continuous growth [
1].
An expending amount of data reveals the importance of an inflammatory microenvironment and stroma in cancer initiation and progression, which brings new directions and approaches to cancer treatment [
2‐
8]. Genetic and functional experiments indicated that inflammatory cells such as tumor-infiltrating monocytes/macrophages, neutrophils, mast cells, eosinophils and activated T and B lymphocytes, as well as stromal fibroblasts contribute to malignancies by releasing growth and survival factors, as well as extracellular proteases, and other proangiogenic factors [
2‐
7]. Melanoma, as with all other cancers, is comprised of a group of heterogeneous cells that co-exist and interact with an infrastructure of other cells (keratinocytes, fibroblasts, endothelial cells, inflammatory cells) and extracellular matrix components (laminin, collagen), growth factors (vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), thrombin), as well as proteases and interleukins involved in invasion (matrix metalloproteinases (MMPs), interleukin-8 (IL-8), urokinase-type plasminogen activator) [
9‐
11]. As described by Haass and Herlyn [
9], alterations in keratinocyte-mediated contact growth inhibition in the skin may drive the malignant transformation of melanocytes. Keratinocytes that are activated by ultraviolet (UV) for example, release interleukins 1, 3, 6 and 8, secrete tumor necrosis factor-α (TNF-α), granulocyte-macrophage colony-stimulating factor, and generate the proinflammatory biolipid platelet-activating factor (PAF), contributing to melanoma development and progression [
12‐
16]. Within the tumor microenvironment, a rapid proliferation of fibroblasts, whose role has been neglected previously, is supported by platelet-derived growth factor (PDGF), bFGF and transforming growth factor-β (TGF-β) produced by melanoma as well as inflammatory cells [
10,
17]. In turn, fibroblasts produce a series of growth factors such as insulin-like growth factor-1, hepatocyte growth factor (HGF)/scatter factor, bFGF, and TGF-β that further support the growth and proliferation of melanoma cells [
10,
17]. Recently, fibroblasts have been shown to remodel the matrix and form “tracks” creating a leading edge for tumor cells invasion [
18]. Strong association has been shown between the recruitment of Tie-2 (an angiopoietin receptor)-expressing monocytes and tumor angiogenesis, and between MMP-9-secreting tumor associated macrophages and tumor cell invasion [
18‐
21]. In addition, platelets and molecular components of the coagulation system and platelet activation pathways have been emerging as critical players of tumor growth and metastasis [
22‐
24]. Overall, it is now believed that cancer cells initiate a pathological cycle, whereby through the constitutive activity of major inflammatory signaling pathways such as nuclear factor-κB (NF-κB), signal transducer and activator of transcription 3 (STAT3) and cyclooxygenases-2 (COX-2)-driven lipid metabolism, they trigger the recruitment and activation of the inflammatory cells, stroma and platelets [
3‐
5,
25‐
29]. In turn, cells within the tumor microenvironment produce inflammatory mediators and angiogenic factors or adhesion-stimulating factors to further amplify the metastatic phenotype [
3‐
5,
25‐
29].