Inhibition of fibronectin accumulation suppresses tumor growth
| Autor: | Verena Klemis, Marin Keimer, Inaam A. Nakchbandi, Hiba Ghura, Norman Hackl, Anja von Au |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Angiogenesis Melanoma Experimental Mice Nude Extracellular matrix Mice Pharmacologic matrix modulation Breast cancer Collagen type I Neoplasms Functional upstream domain (FUD) R1R2 pUR4 medicine Animals Humans Amino Acid Sequence Fibronectin Melanoma RC254-282 Original Research PUR4 biology Cell growth Chemistry Neoplasms. Tumors. Oncology. Including cancer and carcinogens Cancer medicine.disease Xenograft Model Antitumor Assays Peptide Fragments Fibronectins Tumor Burden Mice Inbred C57BL Cancer cell NIH 3T3 Cells Cancer research biology.protein Signal transduction |
| Zdroj: | Neoplasia: An International Journal for Oncology Research, Vol 23, Iss 9, Pp 837-850 (2021) Neoplasia Neoplasia (New York, N.Y.) |
| ISSN: | 1476-5586 |
| DOI: | 10.1016/j.neo.2021.06.012 |
| Popis: | Highlights • Deletion of fibronectin in cancer cells prolongs survival • Pharmacologic inhibition of fibronectin deposition slows down cancer progression in two models • Decreasing fibronectin in the matrix diminishes proliferation in tumors and can serve as an adjuvant therapy Understanding how the extracellular matrix affects cancer development constitutes an emerging research field. Fibronectin and collagen are two intriguing matrix components found in cancer. Large concentrations of fibronectin or collagen type I have been implicated in poor prognosis in patients. In a mouse model, we had shown that genetically decreasing circulating fibronectin resulted in smaller tumors. We therefore aimed to manipulate fibronectin pharmacologically and determine how cancer development is affected. Deletion of fibronectin in human breast cancer cells (MDA-MB-231) using shRNA (knockdown: Kd) improved survival and diminished tumor burden in a model of metastatic lesions and in a model of local growth. Based on these findings, it seemed reasonable to attempt to prevent fibronectin accumulation using a bacterial derived peptide called pUR4. Treatment with this peptide for 10 days in the breast cancer local growth model or for 5 days in a melanoma skin cancer model (B16) was associated with a significant suppression of cancer growth. Treatment aimed at inhibiting collagen type I accumulation without interfering with fibronectin could not affect any changes in vivo. In the absence of fibronectin, diminished cancer progression was due to inhibition of proliferation, even though changes in blood vessels were also detected. Decreased proliferation could be attributed to decreased ERK phosphorylation and diminished YAP expression. In summary, manipulating fibronectin diminishes cancer progression, mostly by suppressing cell proliferation. This suggests that matrix modulation could be used as an adjuvant to conventional therapy as long as a decrease in fibronectin is obtained. Graphical abstract Image, graphical abstract |
| Databáze: | OpenAIRE |
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