Abstract
Tumor cells are confronted to a type I collagen rich environment which regulates cell proliferation and invasion. Biological aging has been associated with structural changes of type I collagen. Here, we address the effect of collagen aging on cell proliferation in a three-dimensional context (3D).We provide evidence for an inhibitory effect of adult collagen, but not of the old one, on proliferation of human fibrosarcoma HT-1080 cells. This effect involves both the activation of the tyrosine kinase Discoidin Domain Receptor 2 (DDR2) and the tyrosine phosphatase SHP-2. DDR2 and SHP-2 were less activated in old collagen. DDR2 inhibition decreased SHP-2 phosphorylation in adult collagen and increased cell proliferation to a level similar to that observed in old collagen.In the presence of old collagen, a high level of JAK2 and ERK1/2 phosphorylation was observed while expression of the cell cycle negative regulator p21CIP1 was decreased. Inhibition of DDR2 kinase function also led to an increase in ERK1/2 phosphorylation and a decrease in p21CIP1 expression. Similar signaling profile was observed when DDR2 was inhibited in adult collagen. Altogether, these data suggest that biological collagen aging could increase tumor cell proliferation by reducingthe activation of the key matrix sensor DDR2.
Highlights
Recent studies have emphasized the importance of bidirectional communication between neoplastic cells and their microenvironment in modulating tumor progression and metastasis, which represent the main uncontrolled problem in cancer therapeutics and the main cause of patient death [1]
The present study demonstrates that Discoidin Domain Receptor 2 (DDR2) - as a key component of type I collagen-cell interaction and signaling - leads to differential regulation of cell proliferation between adult and old 3D collagen matrices
Since we had previously demonstrated by flow cytometry that HT-1080 cells express β1 integrin [23], we investigated whether this integrin mediates the regulation of HT-1080 cell proliferation. siRNA was used to deplete β1 integrin in HT-1080 (Figure 4A), and cell proliferation was assessed in adult and old collagen
Summary
Recent studies have emphasized the importance of bidirectional communication between neoplastic cells and their microenvironment in modulating tumor progression and metastasis, which represent the main uncontrolled problem in cancer therapeutics and the main cause of patient death [1]. The supporting players originating from surrounding normal tissue or from circulation include stromal fibroblasts, immune cells, vascular cells and the extracellular matrix (ECM) that can contribute both positive and negative signals to the tumor cells Because of their pivotal role in tumor development and growth, the tumor microenvironment (TME) components are considered as challenging and attractive therapeutic targets. During cancer initiation and progression, such a complex crosstalk involves dynamic interactions between tumor cells and ECM proteins, well-known to drive fundamental cellular functions including proliferation, differentiation, and motility. These interactions take place during the first steps of primary tumor growth, at the invasive edge for metastatic dissemination and during the initiation of secondary outgrowth in metastatic niches. Type I collagen can be used as a preintravasation microenvironment and can be involved in the initiation of secondary outgrowth in metastatic niches
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