ALCAM shedding at the invasive front of the tumor is a marker of myometrial infiltration and promotes invasion in endometrioid endometrial cancer

Abstract

Endometrial cancer (EC) is the sixth deadliest cancer in women. The depth of myometrial invasion is one of the most important prognostic factors, being directly associated with tumor recurrence and mortality. In this study, ALCAM, a previously described marker of EC recurrence, was studied by immunohistochemistry at the superficial and the invasive tumor areas from 116 EC patients with different degree of myometrial invasion and related to a set of relevant epithelial and mesenchymal markers. ALCAM expression presented a heterogeneous functionality depending on its localization, it correlated with epithelial markers (E-cadherin/β-catenin) at the superficial area, and with mesenchymal markers at the invasive front (COX-2, SNAIL, ETV5, and MMP-9). At the invasive front, ALCAM-negativity was an independent marker of myometrial invasion. This negativity, together with an increase of soluble ALCAM in uterine aspirates from patients with an invasive EC, and its positive correlation with MMP-9 levels, suggested that ALCAM shedding by MMP-9 occurs at the invasive front. In vivo and in vitro models of invasive EC were generated by ETV5-overexpression. In those, we demonstrated that ALCAM shedding was related to a more invasive pattern and that full-ALCAM recovery reverted most of the ETV5-cells mesenchymal abilities, partially through a p-ERK dependent-manner.

EPS364, a Novel Deep-Sea Bacterial Exopolysaccharide, Inhibits Liver Cancer Cell Growth and Adhesion

“…CTNNB1 is generally considered as an intermediate regulator molecule of the FGF19-FGFR4 signaling pathway [ 28 , 36 , 37 , 38 ]. In addition, a lot of studies have shown that the downregulation of CTNNB1 was associated with the downregulations of CDH2, ALCAM and ICAM1, which is consistent with our results [ 31 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ]. The extracellular FGF19-FGFR4 signaling pathway mediates the expression of cell adhesion molecules and regulates specific tumorigenic events, including cancer cell proliferation and metastasis, by activating the expression of downstream intracellular genes [ 35 , 49 , 50 ].…”

“…Studies have shown that the FGF19-FGFR4 signaling pathway was an effective antitumor target via mediating a lot of intracellular molecules [ 52 , 53 ]. CTNNB1 as an intermediate molecule between the FGF19-FGF4 signaling pathway and adhesion molecules such as ICAM1, CDH2 and ALCAM [ 31 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 58 ] was downregulated after EPS364 treatment. Hence, we speculated that EPS364 might target the FGF19-FGF4 signaling pathway to regulate the expression of adhesion molecules.…”

Activated leukocyte cell adhesion molecule expression correlates with the WNT subgroup in medulloblastoma and is involved in regulating tumor cell proliferation and invasion

“…These results seem contradictory, but the difference between ALCAM function in vitro and in vivo indicates that ALCAM may be affected by the surrounding microenvironment. Notably, our results are consistent with those from previous reports regarding other carcinomas in which depletion of ALCAM suppresses cell proliferation and migration in vitro , but the cells demonstrate invasiveness in vivo [ 14 , 16 , 19 , 31 ]. For example, in cell lines of malignant mesothelioma and endometrioid endometrial cancer, proliferation and migration are inhibited in vitro by ALCAM silencing [ 16 , 19 ].…”

“…For example, in cell lines of malignant mesothelioma and endometrioid endometrial cancer, proliferation and migration are inhibited in vitro by ALCAM silencing [ 16 , 19 ]. Nevertheless, ALCAM-negativity at the invasive front of the tumor has been reported as a marker of myometrial invasion in tissue of endometrioid endometrial cancer [ 31 ]. Moreover, in a metastatic melanoma cell line, interfering with endogenous ALCAM through the expression of an amino-terminally truncated ALCAM, which disrupts ALCAM–ALCAM interactions, increases cell invasive growth in skin reconstructions [ 14 ].…”

“…Moreover, in a metastatic melanoma cell line, interfering with endogenous ALCAM through the expression of an amino-terminally truncated ALCAM, which disrupts ALCAM–ALCAM interactions, increases cell invasive growth in skin reconstructions [ 14 ]. The attenuation of ALCAM enhances the invasive abilities of the tumor, which is arguably caused by the reduction of ALCAM-mediated adhesion, resulting in less adhesive and more mobile tumor cells [ 14 , 31 ]. Therefore, the functional role of ALCAM might vary depending on the surrounding microenvironment.…”