Matrix - not the movie

[john]

Interesting article at nature.com

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Most tumours have a dense extracellular matrix that inhibits drug diffusion and serves as a barrier to drug delivery. One of the key components of this barrier is a dense collagen meshwork, although the structure and content of the collagen networks varies between tumour types. Brown et al. have used a non-invasive imaging technique to quantify its density in vivo, allowing researchers to estimate the penetrability of tumours to molecular therapeutics.

Brown et al. used a principle called second harmonic generation (SHG) — an intrinsic fluorescent signal that can be detected without the addition of dyes or other reagents — to obtain high-resolution three-dimensional images of fibrillar collagen in vivo. SHG imaging allowed the authors to view and measure the density of fibrillar structures in different tumour types in mice (image shows SHG signal of collagen in red and cancer cell nuclei in green).

The SHG signal was found to vary among tumour types and was correlated with collagen content, as confirmed by other methods such as immunohistochemical staining of tissue sections. When the authors applied collagenase enzymes to mouse melanomas and imaged them in vivo, the SHG signal gradually faded, indicating the breakdown of the collagen matrix. Furthermore, as the SHG signal decreased, the diffusion co-efficient of a labelled molecular probe increased.

The hormone relaxin, which, among other functions, induces cells to produce matrix metalloproteinases (MMPs), also induced matrix changes that could be detected by SHG. SHG imaging showed that when mice were treated with relaxin, the average length and brightness of pre-existing fibres decreased significantly. Furthermore, the diffusion coefficients of fluorescent molecular probes increased, indicating a 'loosening' of the extracellular matrix. The authors concluded that the matrix of tumours in relaxin-treated mice had a more porous structure, leading to increased molecular mobility.

This simple and rapid technique could be used to determine the density of a tumour's collagen meshwork and estimate its potential for drug delivery, obviating the need for biopsies, tissue sectioning or staining. SHG has also provided insight into the mechanisms by which relaxin alters the tumour matrix, providing a new technology to evaluate alternative strategies for modifying the tumour extracellular matrix.