Metastasis of Neuroendocrine Tumors Are Characterized by Increased Cell Proliferation and Reduced Expression of the ATM Gene

Abstract

Purpose Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare group of tumors with a wide spectrum of clinical behavior. However, there are no known clinically relevant biomarkers to predict metastasis. Experimental Design To investigate differential gene expression signatures of metastatic vs non-metastatic NETs, we studied cell cycle regulatory genes in 19 metastatic and 22 non-metastatic colorectal NETs by PCR arrays. Immunohistochemistry (IHC) and quantitative real-time RT-PCR were performed to verify the results and another set of 38 GEP-NETs were further studied for validation. Results We first delineated six candidate genes for metastasis including ATM , CCND2 , RBL2 , CDKN3 , CCNB1 , and GTSE1 . ATM was negatively correlated with metastatic NETs ( p <0.001) with more than 2-fold change compared to non-metastatic NETs. Overexpression of ATM protein by IHC was strongly correlated with high ATM mRNA levels and low Ki-67 labeling index. Patients with ATM-negativity by IHC showed significantly decreased overall survival than patients with ATM-positivity (median OS, metastatic vs non-metastatic NETs; 2.7 years vs not reached; p = 0.003) and 85.7% of metastatic NETs were ATM-negative. In another validation set of GEP-NETs, decreased mRNA of ATM gene was associated with metastasis and remained significant ( p = 0.023). Conclusions ATM down-regulation was strongly associated with metastatic NETs when compared with non-metastatic NETs and ATM may be a potential predictive marker for metastasis as well as a novel target in metastatic GEP-NETs.

GTSE1 Is a Microtubule Plus-End Tracking Protein That Regulates EB1-Dependent Cell Migration

“…More recently, GTSE1 was identified as one of three cell cycle regulatory genes (along with CDKN3 and Cyclin B1) whose upregulation in gastroenteropancreatic neuroendocrine tumors correlate with metastasis [50]. These observations are consistent with our finding that in breast cancer patients, GTSE1 mRNA expression levels correlate with time to metastasis and tumor grade.…”

“…GTSE1 has been reported as significantly overexpressed in different tumors [48]–[50], suggesting that cell cycle misregulation and/or overexpression of an important GTSE1 activity may play a role in cancer progression. We initially monitored GTSE1 protein levels over a panel of non-transformed and transformed cell lines with different degrees of tumorigenicity (Figure S3A).…”

ATM signalling and cancer

“…127,128 Increased ATM expression is also associated with metastasis and decreased patient survival in neuroendocrine cancer. 129 Although not directly linked to metastasis in these cases, hyperactive ATM increases the damage response and therefore promotes chemoand radioresistance in these cells.…”

High G2 and S‐phase expressed 1 expression promotes acral melanoma progression and correlates with poor clinical prognosis

“…G2 and S‐phase expressed 1 (GTSE1) has been found expressed only in the S and G2 phases of the cell cycle, where it colocalized with tubulin and microtubules, and is overexpressed in lung cancer, breast cancer, and liver cancer . Accumulating evidence indicates that GTSE1 correlates with tumor metastasis and poor clinical outcome in neuroblastoma, neuroendocrine tumors, oral tongue squamous cell carcinoma, and hepatocellular carcinoma . In response to DNA damage, GTSE1 accumulates in the nucleus, where it downregulates p53 and represses its ability to induce apoptosis .…”