Intravital microscopy of cancer invasion, plasticity and integrin function: Targeting cancer resistance


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Peter Friedl1,2
1Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, 2The University of Texas, MD Anderson Cancer Center, Houston, USA

Abstract

The tumour microenvironment contributes to cancer invasion, growth and survival and thereby impacts tumour responses to therapy. We here developed an intravital infrared multiphoton imaging model for the multi-parameter visualisation of collective cancer cell invasion, guidance by the tumour stroma, and short- and long-term resistance to experimental anti-cancer therapy. The data show for orthotopic fibrosarcoma and melanoma xenografts deep invasive growth driven by proliferation concurrent with collective invasion of multicellular strands along the normoxic perivascular stroma. Despite normoxia, perivascular invasion strands were resistant to high-dose hypofractionated irradiation (cumulative dose 20 to 20 Gy) which otherwise was sufficient to induce regression of the tumour main mass. This invasion-associated radioresistance niche comprised several hundreds of cells in close proximity to stromal structures, including collagen, basement vascular and myofibre membranes, and was able to re-establish tumour growth and relapse, thus escaping other imaging modalities but in vivo microscopy. Using simultaneous inhibition of β1 and β3 integrins by RNA interference or combined anti-β1/aV integrin antibody treatment, however, proliferation arrest, anoikis induction was achieved, ablating both tumour lesion and the resistance niche. In conclusion, collective invasion is an important invasion mode in solid tumours into a microenvironmentally privileged survival niche which conveys radioresistance by integrin-dependent signals. These findings show how 'dynamic in vivo cell biology' identifies a key role for integrin-mediated signalling in mediating cross-talk (reciprocity) between the peri-tumour stroma and the tumour cells to mediate altered biology and response to therapy (plasticity).