Angiogenesis in unknown primary tumors

Abstract

Angiogenesis is the process through which new capillariesare formed from pre-existing vessels, and it takes placeduring the embryonic development and in adult life, underphysiological conditions in the female reproductive systemand in pathological conditions, as in the chronic inflam-mation and in tumor growth [1].Tumor angiogenesis has been extensively investigatedin solid and hematological tumors, as well as in pre-malignant conditions, and there are a lot of data regardingthe link between tumor angiogenesis, metastasis, andoverall survival [2–4].Unknown primary tumors (UPT) account for 0.5–7% ofall malignancies [5]. The term UPT characterizes a meta-static disease, most commonly involving liver, lung, and/orbone, for which diagnostic work-up fails to identify a siteof origin. Histologic subtypes of UPT include adenocarci-noma with various degrees of differentiation, squamouscell carcinoma, poorly differentiated carcinoma, and neu-roendocrine cancer [5]. Early dissemination and aggres-siveness represents a fundamental characteristic of thesetumors. Overall, outcome of patients remains poor, with amedial survival ranging from 6 to 12 months [5].Literature data concerning angiogenesis in UPT arescarce. Hillen et al. [6] have compared microvessel densityin liver metastases of UPT with microvessel density inknown primaries and in liver metastases of colon andbreast tumors. They found no indication for a specificbiological role of angiogenesis in the metastatic phenotypeof the UPT. In fact, metastases of UPT showed a highdegree of vascularization and this pattern was also found inmetastatic tumors of primary breast and colon cancer andas in other solid tumors, higher microvascular density wasassociated with worse prognosis. The same authors inanother work demonstrated that immunohistochemicaldetection of vascular endothelial growth factor-A (VEGF-A) and of the endothelial marker CD34 did not have aprognostic significance in patients with UPT [7].Karavasilis et al. [8] assessed immunohistochemicallythe tissue expression of CD34, VEGF, and thrombospon-din-1 (TSP-1) in a retrospective study on 81 patients withUPT and correlated these data with clinicopathologicalparameters. They demonstrated that the expression ofVEGF and TSP-1 was not associated with any clinical orpathological parameter and that tumor microvascular den-sity was higher in tumors classified as unfavorable com-pared to more favorable and was positively associated withVEGF and negatively with TSP-1. The same authors havedemonstrated by immunohistochemistry that matrixmetalloproteinase-2 (MMP-2) and MMP-9 and tissueinhibitor of metalloproteinase-1 (TIMP-1) are widelyexpressed in patients with UPT, suggesting an essentialrole of proteolysis in these tumors, also as factors thatpromote and control angiogenesis [9].Accordingly to above-described evidence, antiangio-genesis has been proposed as a therapeutic strategy in thetreatment of patients with UPT. Hainsworth et al. [10] haveevaluated the efficacy and toxicity of combination inhibi-tion of VEGF and epidermal growth factor receptor(EGFR) with bevacizumab and erlotinib in patients with