High levels of Substance P and its receptor NK-1R in colorectal cancer tissue were significantly associated with lymph node metastasis, advanced tumor stage, and poorer patient survival in a study of 267 patients.
Independent survival predictorSubstance P expression independently predicted survival in multivariate analysis of 267 colorectal cancer patients, alongside lymph node and distant metastasis.
What the researchers found
Both SP and NK1R were significantly upregulated in CRC tissue compared to adjacent normal tissue (P<0.001). High SP expression was significantly associated with lymph node metastasis (P<0.001). High NK1R expression was significantly related to TNM stage (P=0.010) and lymph node metastasis (P=0.019).
SP and NK1R expression were highly correlated with each other (r=0.419, P<0.001), suggesting coordinated upregulation of the signaling pathway in tumors.
Survival analysis showed significantly poorer prognosis for patients with high SP or NK1R expression (P<0.05). Multivariate Cox regression confirmed that SP expression was independently correlated with survival, alongside lymph node metastasis and distant metastasis — meaning SP levels predict outcomes even after accounting for other known prognostic factors.
Why it matters
Colorectal cancer is one of the most common cancers worldwide, and predicting which tumors will spread aggressively is crucial for treatment decisions. Finding that Substance P independently predicts survival adds a potentially useful biomarker to the clinician's toolkit. More importantly, NK-1R antagonists already exist as approved drugs (for nausea), raising the possibility of repurposing them for cancer treatment.
How the study worked
Immunohistochemistry was performed on tissue microarrays containing 267 matched pairs of colorectal cancer and adjacent normal tissue. SP and NK1R expression levels were scored and correlated with clinicopathological features including TNM stage, lymph node metastasis, and distant metastasis. Survival analysis used Kaplan-Meier curves with log-rank tests, and multivariate analysis used Cox proportional hazards regression.
What this study cannot tell us
This is an observational study that demonstrates correlation, not causation — it cannot prove that SP/NK1R directly drives cancer progression. No functional experiments were performed to test whether blocking SP/NK1R signaling would alter tumor behavior. The study population is from a single institution, which may limit generalizability. Immunohistochemistry scoring can be subjective, and the study does not report inter-observer reliability.
How to read the evidence
This is a retrospective observational study with a substantial sample size (267 patients) and appropriate statistical methods including multivariate survival analysis. While it provides strong correlational evidence, the retrospective design and single-center data limit the evidence grade.
When this study was published
Published in 2016, this study established the clinical significance of SP/NK1R in colorectal cancer. Subsequent research has continued to investigate NK-1R antagonists as potential anticancer agents.
The bigger picture
This study adds colorectal cancer to the growing list of tumor types where the Substance P/NK-1R pathway appears to drive progression. The consistent finding across multiple cancer types strengthens the case for NK-1R as a therapeutic target. Combined with preclinical evidence that NK-1R antagonists can inhibit tumor growth, this clinical correlation data provides important translational evidence supporting clinical trials of NK-1R blockade in CRC.
Questions still open
- Could NK-1R antagonists like aprepitant slow colorectal cancer progression in clinical trials?
- Is SP/NK1R expression useful as a biomarker for selecting patients who might benefit from targeted therapy?
- What triggers the upregulation of Substance P in colorectal cancer — is it driven by the tumor itself or the inflammatory microenvironment?
Common questions
Could measuring Substance P in a tumor biopsy help predict how aggressive the cancer is?
Are there drugs that block Substance P's receptor that could treat cancer?
Read the original research
High expression of substance P and its receptor neurokinin-1 receptor in colorectal cancer is associated with tumor progression and prognosis.
OncoTargets and therapy, 9, 3595-602
Citation
Chen, Xiao-Yi; Ru, Guo-Qing; Ma, Ying-Yu; Xie, Jun; Chen, Wan-Yuan; Wang, Hui-Ju; Wang, Shi-Bing; Li, Li; Jin, Ke-Tao; He, Xiang-Lei; Mou, Xiao-Zhou. (2016). High expression of substance P and its receptor neurokinin-1 receptor in colorectal cancer is associated with tumor progression and prognosis.. OncoTargets and therapy, 9, 3595-602. https://doi.org/10.2147/OTT.S102356