Back to Search
Start Over
Stromal-MDM2 Promotes Lung Cancer Cell Invasion through Tumor-Host Feedback Signaling.
- Source :
-
Molecular cancer research : MCR [Mol Cancer Res] 2020 Jun; Vol. 18 (6), pp. 926-937. Date of Electronic Publication: 2020 Mar 13. - Publication Year :
- 2020
-
Abstract
- Tumor-host interactions play a major role in malignancies' initiation and progression. We have reported in the past that tumor cells attenuate genotoxic stress-induced p53 activation in neighboring stromal cells. Herein, we aim to further elucidate cancer cells' impact on signaling within lung cancer stroma. Primary cancer-associated fibroblasts were grown from resected human lung tumors. Lung cancer lines as well as fresh cultures of resected human lung cancers were used to produce conditioned medium (CM) or cocultured with stromal cells. Invasiveness of cancer cells was evaluated by transwell assays, and in vivo tumor growth was tested in Athymic nude mice. We found CM of a large variety of cancer cell lines as well as ex vivo -cultured lung cancers to rapidly induce protein levels of stromal-MDM2. CM of nontransformed cells had no such effect. Mdm2 induction occurred through enhanced translation, was mTORC1-dependent, and correlated with activation of AKT and p70 S6 Kinase. AKT or MDM2 knockdown in fibroblasts reduced the invasion of neighboring cancer cells, independently of stromal-p53. MDM2 overexpression in fibroblasts enhanced cancer cells' invasion and growth of inoculated tumors in mice. Our results indicate that stromal-MDM2 participates in a p53-independent cancer-host feedback mechanism. Soluble cancer-originated signals induce enhanced translation of stromal-MDM2 through AKT/mTORC1 signaling, which in turn enhances the neighboring cancer cells' invasion ability. The role of these tumor-host interactions needs to be further explored. IMPLICATIONS: We uncovered a novel tumor-stroma signaling loop, which is a potentially new therapeutic target in lung cancer and possibly in additional types of cancer.<br /> (©2020 American Association for Cancer Research.)
- Subjects :
- Animals
Apoptosis
Biomarkers, Tumor genetics
Cell Proliferation
Culture Media, Conditioned metabolism
Female
Fibroblasts metabolism
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms genetics
Lung Neoplasms metabolism
Mice
Mice, Nude
Neoplasm Invasiveness
Proto-Oncogene Proteins c-mdm2 genetics
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Biomarkers, Tumor metabolism
Feedback, Physiological
Fibroblasts pathology
Lung Neoplasms pathology
Proto-Oncogene Proteins c-mdm2 metabolism
Stromal Cells metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3125
- Volume :
- 18
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Molecular cancer research : MCR
- Publication Type :
- Academic Journal
- Accession number :
- 32169890
- Full Text :
- https://doi.org/10.1158/1541-7786.MCR-19-0395