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

Abstract

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 role of perineural invasion in predicting survival in patients with primary operable colorectal cancer: A systematic review

“…However, despite the findings of perineural invasion as a strong independent prognostic factor in colorectal cancer; the role of neurogenesis in colorectal cancer still remains unclear [55].…”

Differential survival trends of stage II colorectal cancer patients relate to promoter methylation status of PCDH10, SPARC, and UCHL1

“…[45][46][47] Furthermore, high expression of UCHL1 in cancerassociated fibroblasts was shown as an independent, negative prognostic factor for overall and recurrence-free survival. 45 Albo et al 48 reported that neurogenesis-in which UCHL1 is a key player-in colorectal cancer is involved in tumor progression and associated with poor outcome. In 2008, Mizukami et al 49 proposed that hypomethylation resulting in re-expression of UCHL1 was significantly associated with lymph node metastasis in colorectal cancer.…”

313 Influence of the Neural Microenvironment in Prostate Cancer

“…40 Furthermore, it is likely that nerveepithelial interactions occur in a wide variety of cancers. 26,28 Hence, the use of neurotoxins should be evaluated in other carcinoma models. …”

“…23 Furthermore, nerve-cancer interactions during perineural invasion (PNI) results in a survival advantage for cancer cells. 18,19,24,25 These phenomena have been demonstrated in many other cancer types, [26][27][28][29] demonstrating that nerves have a fundamental role in cancer progression. Addressing the functional significance of nerves and identifying the mechanism by which they influence cancer cell growth may lead to therapeutic approaches that target the neural niche in cancer.…”