Vessel-guided collective cancer invasion in vivo: molecular mechanisms and fate
Final Report Abstract
The tumor microenvironment contributes to cancer invasion, growth and survival and thereby impacts tumor responses to therapy. We here developed an intravital imaging model for the multi-parameter visualization of collective cancer cell invasion, guidance by the tumor stroma, and short- and long-term resistance to experimental anti-cancer therapy. For orthotopic fibrosarcoma and melanoma xenografts the data show deep invasive growth driven by proliferation concurrent with collective invasion of multicellular strands along the normoxic perivascular stroma. Invasion was fast (up to 200 µm per day), non-destructive, and independent of β1 and β3 integrins. Despite normoxia, perivascular invasion strands were resistant to high-dose hypofractionated irradiation, which otherwise was sufficient to induce regression of the tumor main mass. This invasion-associated radioresistance was sensitive to the simultaneous inhibition of β1 and β3 integrins by RNA interference or combined anti-β1/αV integrin antibody treatment due to proliferation arrest and anoikis induction, ablating both tumor lesion and invasion strands. In preliminary work, no effect was obtained by interference with EGFR and CXCR4 alone. In conclusion, collective invasion of solid tumors is an important invasion mode into a microenvironmentally privileged perivascular survival niche which conveys radioresistance by integrin-dependent signals. Consequently, combining dual-integrin inhibition therapy with hypofractionated irradiation may be amenable to clinical cancer treatment of locally destructive and otherwise radioresistant tumor lesions.
