The Expression of the Hypoxia Markers CA9 and CXCR4 Is Correlated with Survival in Patients with Neuroendocrine Tumours of the Ileum

Abstract

Background/Aim: The hypoxia-inducible factor pathway regulates the expression of a diverse group of molecules such as CA9 and CXCR4. Our aim was to investigate the expression of these markers in a series of patients with an ileal neuroendocrine tumour (IET) at various stages of tumorigenesis. Methods: The immunohistochemical expression of CA9 and CXCR4 was examined in 51 patients with a resected IET. A ‘hypoxic score’ was calculated, integrating the expression of both CA9 and CXCR4 (hypoxic score 0: absence of expression of both molecules; hypoxic score 1: expression of CXCR4 and/or CA9). Results were compared to histoprognostic factors (including tumour size, stage and grade, WHO and TNM classifications, presence of vascular or perineural invasion, presence of a fibrotic stroma and microvascular density) and to survival. Results: All tumours were well differentiated. 69% of tumours were less than 25 mm. 46% of tumours largely infiltrated the intestinal wall (≥T3, subserosa and serosa) and 90% were classified as N1 and/or 63% as M1. 57% of tumours were of grade G1, 43% of grade G2. Grade G2 (p = 0.004) and larger tumour infiltration (≥T4; p = 0.03) correlated with lower survival. Hypoxic score 1 correlated with a greater tumour size (p = 0.034), larger tumour infiltration (T3 or T4; p = 0.001), grade G2 (p = 0.046), presence of lymph node metastasis (p = 0.0066) and with lower survival of patients (p = 0.03). Conclusion: The hypoxia-inducible factors CA9 and CXCR4 were found associated to the malignant progression of neuroendocrine tumours of the ileum. Their expression may reflect higher tumour aggressivity.

Carbonic anhydrase IX, a hypoxia-induced catalytic component of the pH regulating machinery in tumors

“…), CA IX modulates expression of EMC components including MMP2, MMP9 and collagen IV (Radvak et al, 2013) and its expression correlates with loss of heterozygozity (LOH) in head and neck carcinoma (De Schutter et al, 2006) and with microvascular density (Couvelard et al, 2005a,b). CA IX also reduces cell-cell adhesion, increases migration and invasion of tumor cells (Svastova et al, 2003; Sansone et al, 2009; Svastova et al, 2012) and its expression and distribution correlates with invasive tumor phenotype (Chen et al, 2005; Rajaganeshan et al, 2009; Deschamps et al, 2012);. CA IX also promotes stemness and correlates with higher histological grades and metastatic disease (Sansone et al, 2007a,b; Storci et al, 2008; Chen et al, 2010; Currie et al, 2013; Fujiwara et al, 2013; Lock et al, 2013).…”

Original paper Morphological and immunohistochemical profile of pancreatic neuroendocrine neoplasms

“…Low vascularity is characteristic for poorly differentiated neuroendocrine carcinomas [109] and can be quantified by non-invasive xenon-inhalation computed tomography [110]. Pathogenetically, hypoxia-inducible factors are associated with malignant progression of well-differentiated neuroendocrine tumours of the ileum [111].…”

Osteotropism of neuroendocrine tumors: role of the CXCL12/CXCR4 pathway in promoting EMT in vitro

“…As compared with normal tissue, both CXCL12 and CXCR4 are overexpressed in NETs, where they signal through the mTOR pathway reinforcing the uncontrolled cell growth [9]. Amongst lung, pancreatic and ileal NETs, increased levels of CXCR4 seem to correlate with higher tumor malignancy and are associated with poor patient outcomes [10–12]. Global gene expression profiling of GOT1 ileal carcinoid cells revealed a marked upregulation of CXCR4 in response to hypoxia, and the agonist stimulation of CXCR4 was able to activate the mitogen-activated protein kinase (MAPK) p42/44 pathway, resulting in increased tumor cell migration [13].…”