To identify the references for this review we did literature searches of MEDLINE using the following key words: ‘tumour’, ‘stroma’, ‘melanoma’, ‘uveal melanoma’, ‘tumour progression’, ‘metastasis’, ‘proteinase’, ‘extracellular matrix’, ‘mesenchymal stem cells’, ‘growth factors’, ‘cytokines’, ‘prognosis’, ‘biological therapy’, ‘pathology’, ‘imaging’, ‘xenograft’, ‘immunohistochemistry’. We did not restrict the results by publication year.
ReviewMelanoma–stroma interactions: structural and functional aspects
Section snippets
Uveal melanoma
An impression of the contour and internal structure of uveal melanoma in patients can be obtained using ultrasonography or magnetic resonance imaging20. Extrascleral extension can also be visualised21. The limited resolution of these techniques does not allow detailed information to be obtained about the tumour stroma, although Silverman and colleagues22 suggest that non-vascular extracellular matrix components associated with microvessels may be the structures identified by ultrasonographic
Molecular players and functional interactions
Melanoma cells interact with their microenvironment through the release of soluble substances and by direct cell-cell contact6, 12, 36, 37. The most important growth factors and cytokines involved in melanoma-stroma cross-talk are illustrated in Figure 5. Autocrine growth factors such as bFGF (basic fibroblast growth factor) produced by melanoma cells stimulate proliferation of the originator cell itself and paracrine growth factors, such as PDGF (platelet-derived growth factor) and VEGF,
Role of the fibroblast
Fibroblasts organise tumour stroma formation by production of extracellular matrix components and are responsible for many of its functions. Here, we focus on interactions between melanoma cells and fibroblasts. Fibroblasts are a rich source of growth factors, such as IGF1, SF (scatter factor), bFGF, and TGFβ, but only after they have been activated6, 12. Tumour growth cannot be sustained unless the tumour cells attract and stimulate fibroblasts, which are the main source of extracellular
Pathobiological implications
So, is it possible to develop an integrated view on melanoma-stroma interactions that affect the biology of tumours? Here we consider some of the key biological aspects: tumour topography, the hierarchy between tumour cells and the stroma, and the pathological mechanisms by which the stroma drives tumour development and progression.
Clinical implications
Do the molecular players and pathomechanisms discussed above provide new instruments or strategies for clinical application? Indeed they do, and here we briefly discuss assessment of prognosis and use of biological therapy.
With the exception of fluorescence imaging in uveal melanoma, no diagnostic applications have so far been identified20, 21, 22. Conventional assessment of prognosis is mainly based on careful tumour staging. This is also true for melanoma63. These assessments could be
Future research
Key issues to address in future research efforts are: (a) what is the participation of bone marrow-derived precursor cells to melanoma stromagenesis? (b) which molecules play a role in the different stages of fibroblast involvement in the tumour stroma? (c) can we visualise the peritumoral zone as an indication of paracrine activity of a tumour? (d) how do the fibrovascular septa promote tumour growth and progression? (e) which growth factors or cytokines are responsible for augmentation of
Search strategy and selection criteria
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