ALK7 expression in prolactinoma is associated with reduced prolactin and increased proliferation

Abstract

Prolactinoma represents the most frequent hormone-secreting pituitary tumours. These tumours appear in a benign form, but some of them can reach an invasive and aggressive stage through an unknown mechanism. Discovering markers to identify prolactinoma proliferative and invading character is therefore crucial to develop new diagnostic/prognostic strategies. Interestingly, members of the TGFβ-Activin/BMP signalling pathways have emerged as important actors of pituitary development and adult function, but their role in prolactinomas remains to be precisely determined. Here, using a heterotopic allograft model derived from a rat prolactinoma, we report that the Activins orphan type I receptor ALK7 is ectopically expressed in prolactinomas-cells. Through immunohistological approaches, we further confirm that normal prolactin-producing cells lack ALK7-expression. Using a series of human tumour samples, we show that ALK7 expression in prolactinomas cells is evolutionary conserved between rat and human. More interestingly, our results highlight that tumours showing a robust expression of ALK7 present an increased proliferation as address by Ki67 expression and retrospective analysis of clinical data from 38 patients, presenting ALK7 as an appealing marker of prolactinoma aggressiveness. Beside this observation, our work pinpoints that the expression of prolactin is highly heterogeneous in prolactinoma cells. We further confirm the contribution of ALK7 in these observations and the existence of highly immunoreactive prolactin cells lacking ALK7 expression. Taken together, our observations suggest that Activin signalling mediated through ALK7 could therefore contribute to the hormonal heterogeneity and increased proliferation of prolactinomas.

Regulation of metabolic homeostasis by the TGF‐β superfamily receptor ALK7

“…As the primary focus of this review is on physiological functions of ALK7 in metabolic regulation, as inferred from in vivo studies in gene-targeted mice, that literature will not be reviewed in any detail here. Although a majority of those studies report pro-apoptotic and/ or anti-proliferative effects of ALK7, or its ligand Nodal, in a variety of cancer cells (e.g., [28,[42][43][44][45][46]), others report opposite effects (e.g., [47][48][49][50]). Antimetastatic and pro-metastatic effects have also been reported [49,51,52].…”

Therapeutic response to pazopanib: case report and literature review on molecular abnormalities of aggressive prolactinomas

“…However, a subset of molecular abnormalities was specifically associated with APRLs ( Table 1 ). These molecular markers include ADAMTS6, MMP-9, TIMP-1, MCM7, ALK7, PTTG1, CUL4A, PITX1, SCN3B, USP8, CRMP1, CCNB1, CENPE, HMGA2, POU6F2, CDKN2A, Galectin-3, DGKZ, VEGF, Rb, and ASK; which were all found to be significantly associated with tumor aggressiveness and invasiveness ( 24 – 27 , 30 , 31 , 35 – 37 , 39 , 41 , 43 , 44 , 48 – 50 , 53 , 54 , 58 , 65 – 68 ). Mismatch repair genes, MSH2 and MSH6, were found to be directly linked to the aggressiveness of both functional and silent prolactinomas ( 16 , 17 ).…”

“…This approach requires a deep understanding of the underlying molecular abnormalities for accurate diagnosis, prognosis, and treatment. Multiple molecular abnormalities have been documented in APRLs, including structural chromosomal abnormalities, genetic mutations, hypermethylation, and surface receptor alterations ( 13 – 27 ). In this study, we present a case of a patient with APRL who harbored multiple molecular abnormalities.…”

Mapping a Circular RNA–microRNA–mRNA-Signaling Regulatory Axis that Modulates Stemness Properties of Cancer Stem Cell Populations in Colorectal Cancer Spheroid Cells

“…IL6ST/GP130 is an integral part of the GP130/Stat signaling pathway, interacting with Stat3 to induce naïve pluripotency and self-renewal [69,74,75]. SKIL/SNON and ACVRLC/AKT7, acting via the Activin/Nodal and TGF-β signaling pathways, are involved in the phosphorylation and association of SMAD2/3 with SMAD4 to enter the nucleus to exert transcriptional activation functions on target genes [70,76,77]. FZD3 and WNT5a regulate β-catenin in the Wnt/β-catenin signaling to contribute to self-renewal, EMT-associated biological processes and differentiation [78][79][80].…”