Abstract
Objective: The aim of the present study was to define the role of luteinizing hormone receptor (LH-R) expression in endometrial cancer (EC), using preclinical mouse models, to further transfer these data to the clinical setting.Materials and Methods: The role of LH-R over-expression was studied using EC cells (Hec1A, e.g., cells with low endogenous LH-R expression) transfected with the LH-R (Hec1A-LH-R). In vitro cell proliferation was measured through the WST-1 assay, whereas cell invasion was measured trough the matrigel assay. The effects of LH-R over-expression in vivo were analyzed in an appropriately developed preclinical mouse model of EC, which mimicked postmenopausal conditions. The model consisted in an orthotopic xenograft of Hec1A cells into immunodeficient mice treated daily with recombinant LH, to assure high levels of LH.Results: In vitro data indicated that LH-R over-expression increased Hec1A invasiveness. In vivo results showed that tumors arising from Hec1A-LH-R cells injection displayed a higher local invasion and a higher number of distant metastases, mainly in the lung, compared to tumors obtained from the injection of Hec1A cells. LH withdrawal strongly inhibited local and distant metastatic spread of tumors, especially those arising from Hec1A-LH-R cells.Conclusion: The over-expression of the LH-R increases the ability of EC cells to undergo local invasion and metastatic spread. This occurs in the presence of high LH serum concentrations.
Highlights
Endometrial carcinoma (EC) is nowadays the most common gynecologic malignancy and the most frequent among infiltrating tumor of the female genital tract [1]
In vivo results showed that tumors arising from Hec1A-luteinizing hormone (LH)-R cells injection displayed a higher local invasion and a higher number of distant metastases, mainly in the lung, compared to tumors obtained from the injection of Hec1A cells
The over-expression of the LH receptor (LH-R) increases the ability of EC cells to undergo local invasion and metastatic spread
Summary
Endometrial carcinoma (EC) is nowadays the most common gynecologic malignancy and the most frequent among infiltrating tumor of the female genital tract [1]. EC is generally considered not aggressive, with a good prognosis and an overall survival (OS) rate of about 80%, there is still a group of patients with a high risk of recurrence and decreased OS [1,2,3] The latter is mainly related to the extra-pelvic spread of the cancer, with the onset of distant metastases, mainly to the lung [4, 5]. Our group better defined the role of LH in tumor progression of EC, demonstrating that LH is able to induce an in vitro invasive phenotype to EC cells [11] Such effect relies on the activation of LH-R and of protein kinase A (PKA), which in turn induces a functional activation of beta 1 integrin receptors and the subsequent secretion of active matrix metalloproteinase-2 ending in the triggering of cell invasiveness [11]
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