Neurogenesis in colorectal cancer is a marker of aggressive tumor behavior and poor outcomes

• Published in: Cancer Vol. 117; no. 21; pp. 4834 - 4845
• Main Authors: Albo, Daniel, Akay, Catherine L., Marshall, Christy L., Wilks, Jonathan A., Verstovsek, Gordana, Liu, Hao, Agarwal, Neeti, Berger, David H., Ayala, Gustavo E.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.11.2011; Wiley-Blackwell
• Subjects: Adenocarcinoma - pathology; Adenocarcinoma - physiopathology; Adult; Aged; Aged, 80 and over; Biological and medical sciences; Cell Line, Tumor; colorectal cancer; Colorectal Neoplasms - pathology; Colorectal Neoplasms - physiopathology; Disease Progression; Disease-Free Survival; Female; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Lymphatic Metastasis; Male; Medical sciences; Middle Aged; nerve density; neuroepithelial interaction in tumor stroma; Neurogenesis; outcomes; Prognosis; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; therapy stratification; Tissue Array Analysis; Tumors; neuroepithelial interaction in tumor stroma; Rectal disease; Prognosis; Colorectal cancer; Stroma; Tumoral marker; Malignant tumor; Density; Colonic disease; Nerve; Cancerology; Treatment; nerve density; outcomes; neurogenesis; Digestive diseases; Intestinal disease; Behavior; therapy stratification; Cancer; High malignancy
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.26117

BACKGROUND: Colorectal cancer staging criteria do not rely on examination of neuronal tissue. The authors previously demonstrated that perineural invasion is an independent prognostic factor of outcomes in colorectal cancer. For the current study, they hypothesized that neurogenesis occurs in colorectal cancer and portends an aggressive tumor phenotype. METHODS: In total, samples from 236 patients with colorectal cancer were used to create a tissue array and database. Tissue array slides were immunostained for protein gene product 9.5 (PGP9.5) to identify nerve tissue. The correlation between markers of neurogenesis and oncologic outcomes was determined. The effect of colorectal cancer cells on stimulating neurogenesis in vitro was evaluated using a dorsal root ganglia coculture model. RESULTS: Patients whose tumors exhibited high degrees of neurogenesis had 50% reductions in 5‐year overall survival and disease‐free survival compared with patients whose tumors contained no detectable neurogenesis (P = .002 and P = .006, respectively). Patients with stage II disease and high degrees of neurogenesis had greater reductions in 5‐year overall survival and disease‐free survival compared with lymph node‐negative patients with no neurogenesis (P = .002 and P = .008, respectively). Patients with stage II disease and high degrees of neurogenesis had lower 5‐year overall survival and disease‐free survival compared with patients who had stage III disease with no neurogenesis (P = .01 and P = .008, respectively). Colorectal cancer cells stimulated neurogenesis and exhibited evidence of neuroepithelial interactions between nerves and tumor cells in vitro. CONCLUSIONS: Neurogenesis in colorectal cancer appeared to play a critical role in colorectal cancer progression. Furthermore, the current results indicated that neurogenesis functions as an independent predictor of outcomes and may play a role in therapy stratification for patients with lymph node‐negative disease. Cancer 2011;. © 2011 American Cancer Society. The results from this study provided evidence of neurogenesis in vitro and in vivo; specifically, the authors report the phenomenon of neurogenesis in colorectal cancer and its association with aggressive stages of colorectal cancer. Neurogenesis was indicative of poor survival and recurrence and was an independent prognostic factor for poor outcomes in patients with colorectal cancer. The authors concluded that neurogenesis offers the potential for better therapy stratification of patients with lymph node‐negative colorectal cancer.