BBB Seminar: Margareta M. Müller

It takes two to tango: The tumor and its stroma

Margareta M. Müller, German Cancer Research Center (DKFZ), Heidelberg, Germany

Inflammation and angiogenesis contribute to tumor development and progression as essential components of the activated tumor microenvironment that is largely orchestrated by tumor cell-derived and additional stroma-derived growth factors. Utilizing the HaCaT skin SCC model we have verified the progression promoting effect of a IL-6 regulated growth factor network including angiogenic factors like VEGF and inflammatory factors like G-CSF, GM-CSF and MCP-1. Neo-expression of VEGF, G-CSF, GM-CSF or IL-6 in previously factor negative cells promotes progression malignancy in vivo accompanied by an enhanced and persistent recruitment of neutrophil-like cells that was followed by an enhanced and persistent angiogenesis. This suggested an essential role of those neutrophil-like cells in the establishment of a pro-tumor inflammatory infiltrate and in the maintenance of persistent angiogenesis and tumor invasion. Confirming the importance of their persistent recruitment depletion of GR-1 expressing inflammatory cells in tumor bearing animals resulted in inhibition of angiogenesis and invasion. This was accompanied by a striking downregulation of stroma derived MMP-9, a protease that together with stromal MMP-13 plays an important role in induction and maintenance of angiogenesis and thus in tumor progression. The essential nature of the persistent stromal activation and angiogenesis as well as of MMP-9 and specifically MMP-13 for malignant progression was confirmed in tumor transplants of MMP-13 deficient mice. Lack of MMP-13 expression induced a phenotypic shift from an invasive, to a pre-malignant, non-invasive tumor phenotype that was associated with a downregulation of angiogenesis and vessel maturation.

Host: Donald Gullberg (donald.gullberg@biomed.uib.no), Department of Biomedicine