Sahai lab

Tumour Cell Biology Laboratory

 Intravital imaging of melanoma cell

Co-culture of cancer cells (darker cells) with stromal fibroblasts (lighter cells) with a signalling molecule shown in green speckles.

Using intravital imaging we identified three different vascular network morphologies within the tumour microenvironment; relatively well organised vessels within the tumour, sprouting networks at the tumour margin and more tortuous vessels further from the tumour.

Scanning Electron Microscopy of an A375 melanoma cell on a collagen-rich matrix.

Figure 1: Scanning Electron Microscopy of an A375 melanoma cell on a collagen-rich matrix. Filopodia are tinted yellow/orange and membrane blebs are tinted magenta/blue.

Endothelial cells are also a key component of the tumour microenvironment. Cerys Manning used intravital imaging to perform longitudinal imaging of melanoma vasculature in vivo. The tumour vasculature is a key part of the microenvironment, providing oxygen and metabolites to the tumour cells. However, current anti-angiogenic therapies have not performed as well as originally hoped in the clinic.

Using intravital imaging we identified three different vascular network morphologies within the tumour microenvironment; relatively well organised vessels within the tumour, sprouting networks at the tumour margin and more tortuous vessels further from the tumour. Our novel method for longitudinal imaging highlighted interesting transitions between these different vascular networks not previously observed in the conventional single time point analysis.

Given the poor clinical response to anti-angiogenic therapies, we used the clinically approved anti-angiogenic agent, Sunitinib, to test if the different vascular regions we identified responded differently to therapy. We showed that although treatment with Sunitinib reduced overall tumour vascular density and slowed tumour growth, Sunitinib had no significant effect on the angiogenic sprouting behaviour of the vasculature at the tumour margin. Therefore, we have demonstrated that within tumours that are broadly responsive to Sunitinib, there are pre-existing refractory microenvironments.

Furthermore, we showed that these pre-existing refractory microenvironments were high in protease activity, CXCL12, FGF-2 and HGF. We propose that these micro-environments may account for the partial and heterogeneous response to anti-angiogenic therapy in the clinical setting.