Elsevier

The Lancet Oncology

Volume 3, Issue 1, January 2002, Pages 35-43
The Lancet Oncology

Review
Melanoma–stroma interactions: structural and functional aspects

https://doi.org/10.1016/S1470-2045(01)00620-9Get rights and content

Summary

Cutaneous melanomas are notorious for their tendency to metastasise. Because the tumour microenvironment plays an important part in tumour development and progression, we review the structural and functional aspects of interactions between melanoma and the stroma. We emphasise fibrovascular patterns (both in uveal and cutaneous melanoma), cellular and extracellular composition of the stroma, and the molecules involved. Also, we discuss functional interactions, focusing on melanoma-fibroblast cross-talk by soluble factors and by direct cell-cell contact. On the basis of recent findings we propose that involvement of fibroblasts in melanoma-stromagenesis occurs through different stages: recruitment, activation, and conversion to myofibroblasts, or differentiation to fibrocytes. We reason that this involvement is topographically linked to different areas in and around the tumour, and hypothesise that stromal activation, as seen in tumor ulceration or immunological regression in melanoma, stimulates tumour progression.

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

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.

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