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G. Pidgeon
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P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.02-069 - Targeting Neuropilin-1 in NSCLC (ID 10205)
09:30 - 09:30 | Author(s): G. Pidgeon
- Abstract
Background:
Neuropilin-1 (NP1) is expressed by a wide variety of human tumour cell lines and diverse human neoplasms, and is implicated in mediating the effects of VEGF on the proliferation, survival and migration of cancer cells. It is extensively expressed in tumour vasculature, where NP1 over-expression is associated with tumour progression and poor clinical outcome. In this study, we examined the effects of targeting NP1 in NSCLC both in vitro and in vivo.
Method:
A panel of NSCLC cell lines (H460, H647, A549 and SKMES) were screened for NP1 at the mRNA and protein levels by RT-PCR and Western blotting, respectively. Cellular expression and localisation of NP1 was further examined by immunocytochemistry, while a panel of retrospective resected lung tumours and matched normal tissues were stained by immunohistochemistry. The effects of targeting NP1 on cell proliferation (BrdU ELISA), apoptosis (FACS, HCS) and downstream survival signalling pathways (Western Blot) were examined under normoxic and hypoxic (0.1% O~2~) cell growth using anti-NP1 neutralising antibodies. Cell survival was assessed in response to treatment of NSCLC cells with a range of chemotherapeutic agents in combination with NP1 neutralising antibodies. Using a human xenograft model, tumour growth studies were carried out in nude mice following subcutaneous injection of NP1 over-expressing cells relative to empty vector controls.
Result:
All lung cancer cell lines examined expressed NP1 with the exception of the H460 cell line. Immunocytochemistry analysis confirmed cellular expression and localisation of this receptor, particularly in the leading edges of migrating cells, suggesting a possible role in cell migration. In a small cohort of resected NSCLC patients, tumour expression of NP1 was high relative to their matched normal lung tissues in adenocarcinoma, squamous cell and large cell neuroendocrine carcinomas. Cell proliferation and apoptosis were significantly altered in NSCLC cells expressing NP1. While hypoxia induced the expression of NP1, treatment of cells with NP1 neutralising antibodies reduced hypoxia-mediated cell proliferation and decreased expression of PI3K and MAPK signalling pathways. In a preliminary study, treatment with NP1 neutralising antibodies sensitised NSCLC cells to the cytotoxic effects of chemotherapy. In vivo, H460 cells over-expressing NP1 significantly increased tumour growth in NOD/SCID mice relative to empty vector controls.
Conclusion:
These data suggest a role for the Neuropilin-1 receptor in promoting cell survival and tumour growth in NSCLC and may offer potential as a therapeutic biological strategy in lung cancer.
