Nestin predicts a favorable prognosis in early ampullary adenocarcinoma and functions as a promoter of metastasis in advanced cancer

Abstract

Nestin exhibits stemness characteristics and is over-expressed in several types of cancers. Downstream signaling of nestin [cyclin-dependent kinase 5 (CDK5) and Ras-related C3 botulinum toxin substrate 1 (Rac1)] functions in cancer to modulate cellular behaviors. We studied the function of nestin in ampullary adenocarcinoma. Immunohistochemistry (IHC), reverse transcription-polymerase chain reaction, and cDNA microarray of nestin in ampullary adenocarcinoma was compared with normal duodenum. CDK5 and Rac1 were assessed by western blotting. We hypothesized that nestin/CDK5/Rac1 signaling behaves different in early and advanced cancer. We found that the presence of nestin mRNA was increased in the early stages of cancer (T2N0 or T3N0) and advanced cancer with lymph node metastasis (T4N1). A total of 102 patients were enrolled in the IHC staining. Weak nestin expression was correlated with favorable characteristics of cancer, decreased incidence of local recurrence and lower risk of recurrence within 12 months after surgery. Patients with weak nestin expression had the most favorable recurrence-free survival rates. Patients with mild to strong nestin expression exhibited an advanced behavior of cancer and increased possibility of cancer recurrence. The reciprocal expression of nestin and RAC1 were explored using a cDNA microarray analysis in the early stages of ampullary adenocarcinoma. Increased level of CDK5 with simultaneously decreased expression of Rac1 was detected by western blotting of ampullary adenocarcinoma in patients without cancer recurrence. The activation of multiple oncogenic pathways, combined with the stemness characteristics of nestin, formed a complex network in advanced ampullary adenocarcinoma. Our study demonstrated that nestin performs a dual role in ampullary adenocarcinoma. Appropriate amount of nestin enhances CDK5 function to suppress Rac1 and excessive nestin/CDK5 participates in multiple oncogenic pathways to promote cancer invasiveness. Inhibiting nestin in patients who exhibit nestin-overexpressed ampullary adenocarcinoma may be a method of preventing cancer recurrence.

Nestin: A biomarker of aggressive uterine cancers

“…High nestin expression is more common in aggressive uterine cancers, but appears to be more predictive of poor outcome in patients with lower risk, including those with early stage disease and G1/G2 endometrioid histologies with and without LVSI. These findings are consistent with the mechanistic studies of nestin and clinical outcome assessments of nestin expression in other cancers [20,22,25,26]. It is a testable and biologically relevant protein that may have utility as a triage tool to identify lower risk patients who may require more aggressive treatment.…”

“…Nestin is a regulator of TGF-β [17,18] and in vitro experiments have demonstrated that it plays a role in invasion, metastasis, and angiogenesis [17,22]. The association of nestin expression with prognosis has been demonstrated in ganglioglioma, ovarian, head and neck, prostate, bladder, and pancreatic cancer [20,22,25,26], and from the present work, in uterine cancer. Nestin may have utility as a theragnostic triage companion test and opportunity for further risk stratification for clinical management.…”

An immunohistochemical study of cyclin-dependent kinase 5 (CDK5) expression in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC): a possible prognostic biomarker

“…To date, the expression of CDK5 was investigated in several cancers [ 13 , 15 , 17 ]. Higher expression of CDK5 was observed in hepatocellular carcinoma, ampullary adenocarcinoma, breast cancer, and medullary thyroid carcinoma, and Zachary et al confirmed the expression of CDK5 was upregulated in colorectal, head/neck, breast, lung, ovarian, lymphoma, prostatic, sarcoma, myeloma, and bladder cancers via the Oncomine microarray online data mining software [ 11 , 12 , 18 , 28 ]. However, downregulated expression of CDK5 was observed in gastric cancer.…”

“…CDK5 regulates DNA damage response via phosphorylating Ataxia telangiectasia mutated (ATM) kinase and thereby affecting its downstream signal pathways which was crucial to progression of hepatocellular carcinoma [ 12 ]. In ampullary adenocarcinoma, over expression of nestin/CDK5 was involved in several oncogenic pathways (the activation of NOTCH, TGF-β1, or PDGFR pathways) that facilitated invasiveness of cancer [ 28 ]. In breast cancer, CDK5 takes part in epithelial-mesenchymal transition induced by TGF-β1which is vital for tumor metastasis [ 11 ].…”

Laparoscopic Surgery for Large Ovarian Cysts-Review

“…It plays a critical role in cancer cell migration, invasion, angiogenesis, and metastasis both in vitro and in vivo [12][13][14][15]. Nestin confers a poor prognosis in a number of cancers [11,[16][17][18], but had not yet been explored in uterine cancer.…”