Book of abstract 2008

Inflammation, angiogenesis and tumor invasion: the role of proteolytic
enzymes in the malignant progression of skin SCCs
Wiltrud Lederle, Silvia Vosseler, Dennis Dauscher, Bettina Hartenstein, Zena Werb, Peter
Angel, Margareta M. Müller
Group Tumor and Microenvironment, German Cancer Research Center (DKFZ), INF 280, D-69120
Heidelberg, Germany
Tumor progression is significantly controlled by an activated tumor promoting
microenvironment that is initially induced by tumor cell derived growth factors. We
provide evidence that an essential contribution of these growth factors to promoting
malignant progression lies in the induction of a tumor supporting inflammatory infiltrate
as well as in the activation of tumor- and stroma-derived MMPs.
We have generated a growth factor driven tumor progression model of skin SCCs
encompassing each step of progression. Induced expression of PDGF promotes benign
tumor growth, whereas expression of VEGF, IL-6 and G-CSF induce malignant tumor
growth with increasing malignancy, respectively. While benign tumor growth is associated
with a transient inflammatory cell recruitment and angiogenesis, malignant progression
induced by VEGF, IL-6 or G-CSF leads to a persistent recruitment of neutrophils followed
by persistent angiogenesis. This is associated with a strong and persistent accumulation of
MMP-9, which co-localizes with neutrophil and a low level of stromal MMP-13 that seems
strictly associated with tumor invasion. Co-expression of VEGF, IL-6, G-CSF and GM-
CSF induce an enhanced malignant and spontaneously metastasizing tumor phenotype,
with high expression of tumor derived MMP-1 and MMP-14 as well as of stromal MMP-9
and MMP-13. Interestingly, lack of MMP-9 expressing neutrophils, achieved by neutrophil
depletion, as well as lack of MMP-13 inhibit angiogenesis and tumor invasion. While
neutrophils depletion seems to change the tumor supporting nature of the inflammatory
cell infiltrate and inhibits already early stages of angiogenesis, lack of MMP-13 in MMP-13
knock out mice does not inhibit the initial angiogenic response that occurs in both benign
and malignant
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tumors. Instead it inhibits the persistent angiogenesis as well as the tumor
invasion that characterizes malignant tumor growth. This is associated with a reduction
of VEGF expression in late stages of tumor transplantation. Thus, we hypothesize that of
stromal MMP-9 as expressed by neutrophils contributes to the initial angiogenic response
that accompanies both benign and malignant tumor growth. In contrast stromal MMP-13
seems essential for the maintenance of angiogenesis and the induction of tumor invasion.
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