ArticleNeoplasia (New York, N.Y.)2012
p16INK4A represses breast stromal fibroblasts migration/invasion and their VEGF-A-dependent promotion of angiogenesis through Akt inhibition.
Article in Neoplasia (New York, N.Y.), 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
26 citing papers in PubMed, 33 citations in OpenAlex.
- Crosstalk of methylation and tamoxifen in breast cancer (Review).Molecular medicine reports · 2024Review
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- Identification of the prognostic value of elevated ANGPTL4 expression in gallbladder cancer-associated fibroblasts.Cancer medicine · 2021Article
- CDKN2A inhibits cell proliferation and invasion in cervical cancer through LDHA-mediated AKT/mTOR pathway.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2021Article
- Deletion of p16 accelerates fracture healing in geriatric mice.American journal of translational research · 2021Article
- Crosstalk between Tumor-Infiltrating Immune Cells and Cancer-Associated Fibroblasts in Tumor Growth and Immunosuppression of Breast Cancer.Journal of immunology research · 2021Review
- Cancer-associated fibroblast regulation of tumor neo-angiogenesis as a therapeutic target in cancer.Oncology letters · 2019Review
- Anti-tumor effect of CDK inhibitors on CDKN2A-defective squamous cell lung cancer cells.Cellular oncology (Dordrecht, Netherlands) · 2018Article
- Hypoxic Signalling in Tumour Stroma.Frontiers in oncology · 2018Review
- Ozone oil promotes wound healing by increasing the migration of fibroblasts via PI3K/Akt/mTOR signaling pathway.Bioscience reports · 2017Article
- Expression of the tumor suppressor gene p16, and lymph node metastasis in patients with ovarian cancer.Oncology letters · 2017Article
- Loss of p16Oncotarget · 2017Article
- Dual role for p16 in the metastasis process of HPV positive head and neck cancers.Molecular cancer · 2017Article
- Genetic alterations and epigenetic alterations of cancer-associated fibroblasts.Oncology letters · 2017Article
- Inhibitory Effect of Ginseng on Breast Cancer Cell Line Growth Via Up-Regulation of Cyclin Dependent Kinase Inhibitor, p21 and p53Asian Pacific journal of cancer prevention : APJCP · 2016Article
- An overview of long non-coding RNAs in ovarian cancers.Oncotarget · 2016Review
- The protective effect of p16(INK4a) in oral cavity carcinomas: p16(Ink4A) dampens tumor invasion-integrated analysis of expression and kinomics pathways.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2015Article
- Hematopoietic stem cell-derived adipocytes and fibroblasts in the tumor microenvironment.World journal of stem cells · 2015Review
- Article
- Effects of Hypoxia, Surrounding Fibroblasts, and p16 Expression on Breast Cancer Cell Migration and Invasion.Journal of Cancer · 2015Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Stromal fibroblasts, the most abundant and probably the most active cellular component of breast cancer-associated stroma, become active and promote angiogenesis through paracrine effects. However, it still unclear how these processes are regulated. Here, we have shown that down-regulation of the tumor suppressor p16(INK4A) protein enhances the migration/invasion abilities of breast stromal fibroblasts, which form dendritic network of extensions into matrigel. Furthermore, we present clear evidence that p16(INK4A) represses the expression/secretion of the proangiogenesis protein vascular endothelial growth factor A (VEGF-A). Consequently, p16(INK4A)-deficient breast stromal fibroblasts and mouse embryonic fibroblasts enhanced endothelial cell differentiation into capillary-like structures in a paracrine manner. This effect was suppressed by adding bevacizumab, a specific VEGF-A inhibitor. Additionally, p16(INK4A)-defective mouse embryonic fibroblasts enhanced angiogenesis in breast cancer xenografts in mice. Furthermore, we have shown that p16(INK4A) suppresses the Akt/mammalian target of rapamycin (mTOR) signaling pathway and its downstream effector hypoxia-inducible factor 1-alpha (HIF-1α), which transactivates VEGF-A. Consequently, Akt inactivation suppressed both the p16(INK4A)-dependent autocrine effect on fibroblast migration/invasion and the paracrine effect on angiogenesis, showing the important role of this protein kinase in mediating the various effects related to p16(INK4A) deficiency. These results indicate that p16(INK4A) is an efficient inhibitor of the migration/invasion abilities of breast stromal fibroblasts and also their paracrine proangiogenic effects, through inhibition of Akt. Therefore, pharmacologic restoration of p16(INK4A) level in stromal fibroblasts may be exploited as therapeutic strategy to help eradicate tumor cells and/or prevent their recurrence, through suppressing cell non-autonomous procarcinogenic mediators.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.