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- Title
Targeting the HGF/c-MET pathway in advanced pancreatic cancer: a key element of treatment that limits primary tumour growth and eliminates metastasis.
- Authors
Xu, Zhihong; Pang, Tony C. Y.; Liu, Adele C.; Pothula, Srinivasa P.; Mekapogu, Alpha Raj; Perera, Chamini J.; Murakami, Takashi; Goldstein, David; Pirola, Romano C.; Wilson, Jeremy S.; Apte, Minoti V.
- Abstract
<bold>Background: </bold>Stromal-tumour interactions facilitate pancreatic cancer (PC) progression. The hepatocyte growth factor (HGF)/c-MET pathway is upregulated in PC and mediates the interaction between cancer cells and stromal pancreatic stellate cells (PSCs). This study assessed the effect of HGF/c-MET inhibition plus gemcitabine (G) on the progression of advanced PC.<bold>Methods: </bold>Orthotopic PC was produced by implantation of luciferase-tagged human cancer cells + human PSCs into mouse pancreas. Tumours were allowed to develop without treatment for 4 weeks. Mice were then treated for 6 weeks with one of the following: IgG, G, HGF inhibitor (Hi), c-MET inhibitor (Ci), Hi + Ci, Hi + G, Ci + G, or Hi + Ci + G.<bold>Results: </bold>Bioluminescence imaging showed similar tumour sizes in all mice at the initiation of treatments. Triple therapy (Hi + Ci + G): (1) completely eliminated metastasis; (2) significantly reduced tumour size as assessed by bioluminescence and at necropsy; (3) significantly reduced proliferating cancer cell density and stem cell marker DCLK1 expression in tumours. In vitro 3D culture studies supported our in vivo findings.<bold>Conclusion: </bold>Even at an advanced disease stage, a two-pronged approach, targeting (a) HGF/c-MET with relevant inhibitors and (b) cancer cells with chemotherapy, completely eliminated metastasis and significantly decreased tumour growth, suggesting that this is a promising treatment approach for PC.
- Publication
British Journal of Cancer, 2020, Vol 122, Issue 10, p1486
- ISSN
0007-0920
- Publication type
journal article
- DOI
10.1038/s41416-020-0782-1