The chemokine (CCL2-CCR2) signaling axis mediates perineural invasion Journal Article
| Authors: | He, S.; Chen, C. H.; Deborde, S.; Bakst, R. L.; Chernichenko, N.; Mcnamara, W. F.; Lee, S. Y.; Barajas, F.; Yu, Z.; Al-Ahmadie, H. A.; Wong, R. J. |
| Article Title: | The chemokine (CCL2-CCR2) signaling axis mediates perineural invasion |
| Abstract: | Perineural invasion is a form of cancer progression where cancer cells invade along nerves. This behavior is associated with poor clinical outcomes; therefore, it is critical to identify novel ligand-receptor interactions between nerves and cancer cells that support the process of perineural invasion. A proteomic profiler chemokine array was used to screen for nervederived factors secreted from tissue explants of dorsal root ganglion (DRG), and CCL2 was identified as a lead candidate. Prostate cancer cell line expression of CCR2, the receptor to CCL2, correlated closely with MAPK and Akt pathway activity and cell migration towards CCL2 and DRG. In vitro nerve and cancer coculture invasion assays of perineural invasion demonstrated that cancer cell CCR2 expression facilitates perineural invasion. Perineural invasion is significantly diminished in coculture assays when using DRG harvested from CCL2-/- knockout mice as compared with control CCL2 +/ + mice, indicating that CCR2 is required for perineural invasion in this murine model of perineural invasion. Furthermore, 20 of 21 (95%) patient specimens of prostate adenocarcinoma with perineural invasion exhibited CCR2 expression by immunohistochemistry, while just 3 of 13 (23%) lacking perineural invasion expressed CCR2. In summary, nerve-released CCL2 supports prostate cancer migration and perineural invasion though CCR2-mediated signaling. Implications: These results reveal CCL2-CCR2 signaling as a key ligand-receptor mechanism that mediates cancer cell communication with nerves during perineural invasion and highlight a potential future therapeutic target. ©2014 AACR. |
| Keywords: | immunohistochemistry; signal transduction; mitogen activated protein kinase; protein kinase b; controlled study; human tissue; protein expression; human cell; nonhuman; mouse; animal tissue; mus; metastasis; animal experiment; animal model; enzyme activation; in vitro study; explant; correlation analysis; cancer cell; murinae; cell migration; prostate adenocarcinoma; chemokine receptor ccr2; perineural invasion; monocyte chemotactic protein 1; knockout mouse; coculture; molecular pathology; spinal ganglion; tumor invasion; human; priority journal; article; prostate cancer cell line |
| Journal Title: | Molecular Cancer Research |
| Volume: | 13 |
| Issue: | 2 |
| ISSN: | 1541-7786 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2015-02-01 |
| Start Page: | 380 |
| End Page: | 390 |
| Language: | English |
| DOI: | 10.1158/1541-7786.mcr-14-0303 |
| PROVIDER: | scopus |
| PMCID: | PMC4336839 |
| PUBMED: | 25312961 |
| DOI/URL: | |
| Notes: | Export Date: 2 April 2015 -- Source: Scopus |
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21Chernichenko -
412Wong -
42Chen -
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He -
656Al-Ahmadie -
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He -
20Deborde -
3
Barajas -
7
Mcnamara -
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Lee
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