Neuropeptide Substance P Drives Endometrial Cancer Growth and Spread — Blocked by NK-1R Antagonist | Research

The takeaway

Substance P promotes endometrial cancer cell proliferation and invasion by inducing MMP-9 and VEGF-C, but these effects can be blocked by an NK-1R receptor antagonist.

NK-1R antagonist blocks cancer effects
Substance P promoted endometrial cancer cell proliferation and invasion by turning on MMP-9 and VEGF-C — but all of these cancer-driving effects were inhibited when the NK-1R receptor was blocked.

What the researchers found

Both substance P (SP) and its receptor NK-1R were expressed at significantly higher levels in endometrial adenocarcinoma tissues and Ishikawa cancer cells compared to normal endometrium.

Substance P treatment significantly enhanced Ishikawa cell proliferation (measured by MTT assay) and invasion through matrigel barriers (transwell assay). Mechanistically, SP induced upregulation of MMP-9 (matrix metalloproteinase 9, which degrades extracellular matrix to enable invasion) and VEGF-C (vascular endothelial growth factor C, which promotes lymphangiogenesis and metastasis). All of these effects were blocked when an NK-1R antagonist was applied.

Why it matters

Endometrial cancer is the most common gynecological cancer in developed countries, with rising incidence linked to the obesity epidemic. Current treatments — surgery, radiation, hormonal therapy — have significant limitations for advanced disease. If substance P drives cancer progression through a druggable receptor (NK-1R), existing NK-1R antagonists (like aprepitant, already approved for chemotherapy-induced nausea) could potentially be repurposed as anti-cancer agents for endometrial carcinoma.

How the study worked

SP and NK-1R expression levels were measured in endometrial adenocarcinoma tissue samples and the Ishikawa endometrial cancer cell line using real-time quantitative PCR and Western blot analysis. Cell proliferation was assessed using MTT assays after SP treatment. Invasive capacity was evaluated using transwell matrigel invasion assays. MMP-9 and VEGF-C expression changes after SP exposure were quantified by PCR and Western blot. NK-1R antagonist was applied to test whether blocking the receptor inhibited SP's pro-cancer effects.

What this study cannot tell us

Only one endometrial cancer cell line (Ishikawa) was used, which may not represent the diversity of endometrial cancers. No animal models or in vivo experiments were conducted to confirm the findings in living organisms. The number of human tissue samples compared is not specified in the abstract. The specific NK-1R antagonist used and its concentration are not detailed. The study does not assess whether blocking SP/NK-1R affects normal endometrial cells or would have side effects.

How to read the evidence

This is a preclinical in vitro study using a single cancer cell line and human tissue samples. The consistent findings across multiple assays (proliferation, invasion, protein expression) strengthen the evidence for the SP/NK-1R mechanism. However, the lack of in vivo validation, use of only one cell line, and absence of clinical data limit the evidence to early proof-of-concept.

When this study was published

Published in 2016, this study contributed to growing evidence for substance P's role in gynecological cancers. Research into NK-1R antagonists as anti-cancer agents has continued to expand since this publication.

The bigger picture

Substance P's role in cancer is part of a broader recognition that neuropeptides — once thought to function only in the nervous system — play important roles in tumor biology. The SP/NK-1R axis has been implicated in breast, colon, lung, and pancreatic cancers in addition to endometrial cancer. NK-1R antagonists like aprepitant are already FDA-approved for other indications, making drug repurposing a realistic possibility. This study adds endometrial cancer to the growing list of tumors where substance P signaling may be a therapeutic target.

Questions still open

Could the already-approved NK-1R antagonist aprepitant be repurposed as an adjunctive therapy for endometrial cancer?
Do circulating substance P levels correlate with endometrial cancer stage or prognosis in patients?
Does the SP/NK-1R pathway interact with hormonal (estrogen/progesterone) signaling in endometrial cancer, given the tissue's hormone sensitivity?

Common questions

What is substance P and why is it found in cancer tissue?

Substance P is a small peptide (11 amino acids) primarily known for transmitting pain signals in the nervous system. However, cancer cells can also produce and respond to substance P through its receptor NK-1R. In this study, endometrial cancer tissue had significantly more substance P and NK-1R than normal tissue. The peptide appears to help cancer cells grow faster and invade surrounding tissues by activating proteins that break down barriers (MMP-9) and promote blood vessel growth (VEGF-C).

Are there already drugs that could block substance P in cancer?

Yes — NK-1R antagonists like aprepitant (Emend) are already FDA-approved for preventing chemotherapy-induced nausea. Since they block the same receptor that substance P uses to promote cancer growth, they could potentially be repurposed for anti-cancer use. However, this would require clinical trials to confirm safety and efficacy specifically for cancer treatment.

Read the original research

Substance P Promotes the Progression of Endometrial Adenocarcinoma.

International journal of gynecological cancer : official journal of the International Gynecological Cancer Society, 26(5), 845-50

View on PubMed ↗Publisher’s paper ↗

Citation

Ma, Jing; Yuan, Shifa; Cheng, Jianxin; Kang, Shan; Zhao, Wenhong; Zhang, Jie. (2016). Substance P Promotes the Progression of Endometrial Adenocarcinoma.. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society, 26(5), 845-50. https://doi.org/10.1097/IGC.0000000000000683