<scp>IGF</scp> signalling in germ cells and testicular germ cell tumours: roles and therapeutic approaches

Selfe, Joanna; Shipley, Janet

doi:10.1111/andr.12658

Cited by 8 publications

(6 citation statements)

References 106 publications

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“…However, the reported results of the NT2D1 cell invasion assays strongly indicate that the autologous microenvironment could positively or negatively modulate the cellular response to pathway inhibitors, and should be studied as a fundamental co-factor necessary for the success of inhibitor-based therapies. Taken together, these results indicate that the study of the testicular secretome of TGCT patients could be a useful tool to identify the possible interaction among PI3K inhibitors, i.e., those used for the targeted therapy proposed by [ 26 ] Selfe and coworkers, and the signaling pathways simultaneously present in the testicular niche that can modulate the effect of the inhibitors, leading to paradoxical effects. This investigation would help to better understand the interaction among pathway inhibitors and the cancer microenvironment and could allow for the prediction of responders and not-responders to TGTC personalized targeted therapies.…”

Section: Discussionmentioning

confidence: 78%

“…We previously demonstrated that NT2D1 cells do not express and secrete HGF [ 8 ]; therefore, as far as we know, there is not an autocrine contribution to c-MET activation in this cell line. In line with this result [ 25 , 26 ], Selfe and coworkers studied the constitutive phosphorylation of tyrosine-kinase receptors in TGCT-derived cell lines and concluded that the c-MET receptor is not constitutively activated in NT2D1 cells.…”

Section: Resultsmentioning

confidence: 86%

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The PI3K/AKT Pathway Is Activated by HGF in NT2D1 Non-Seminoma Cells and Has a Role in the Modulation of Their Malignant Behavior

Gesualdi

Leonetti

Cucina

et al. 2020

IJMS

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Overactivation of the c-MET/HGF system is a feature of many cancers. We previously reported that type II testicular germ cell tumor (TGCT) cells express the c-MET receptor, forming non-seminomatous lesions that are more positive compared with seminomatous ones. Notably, we also demonstrated that NT2D1 non-seminomatous cells (derived from an embryonal carcinoma lesion) increase their proliferation, migration, and invasion in response to HGF. Herein, we report that HGF immunoreactivity is more evident in the microenvironment of embryonal carcinoma biopsies with respect to seminomatous ones, indicating a tumor-dependent modulation of the testicular niche. PI3K/AKT is one of the signaling pathways triggered by HGF through the c-MET activation cascade. Herein, we demonstrated that phospho-AKT increases in NT2D1 cells after HGF stimulation. Moreover, we found that this pathway is involved in HGF-dependent NT2D1 cell proliferation, migration, and invasion, since the co-administration of the PI3K inhibitor LY294002 together with HGF abrogates these responses. Notably, the inhibition of endogenous PI3K affects collective cell migration but does not influence proliferation or chemotactic activity. Surprisingly, LY294002 administered without the co-administration of HGF increases cell invasion at levels comparable to the HGF-administered samples. This paradoxical result highlights the role of the testicular microenvironment in the modulation of cellular responses and stimulates the study of the testicular secretome in cancer lesions.

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Section: Discussionmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 86%

The PI3K/AKT Pathway Is Activated by HGF in NT2D1 Non-Seminoma Cells and Has a Role in the Modulation of Their Malignant Behavior

Gesualdi

Leonetti

Cucina

et al. 2020

IJMS

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“…We studied c-MET and HGF expression even in seminoma and non-seminoma derived cell lines (TCam-2, NCCIT, NT2D1), demonstrating that HGF is not expressed by all these cell lines [4]. Accordingly, previous data from Selfe [6,7] and coworkers demonstrated that the c-MET receptor is expressed but not constitutively activated in the same cell lines. We also demonstrated that the non-seminoma cell line NT2D1 is the best responsive to the administration of exogenous HGF, with respect to TCam-2 and NCCIT cell lines [4].…”

Section: Introductionmentioning

confidence: 72%

ERK Signaling Pathway Is Constitutively Active in NT2D1 Non-Seminoma Cells and Its Inhibition Impairs Basal and HGF-Activated Cell Proliferation

et al. 2023

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c-MET/hepatocyte growth factor (HGF) system deregulation is a well-known feature of malignancy in several solid tumors, and for this reason this system and its pathway have been considered as potential targets for therapeutic purposes. In previous manuscripts we reported c-MET/HGF expression and the role in testicular germ cell tumors (TGCTs) derived cell lines. We demonstrated the key role of c-Src and phosphatidylinositol 3-kinase (PI3K)/AKT adaptors in the HGF-dependent malignant behavior of the embryonal carcinoma cell line NT2D1, finding that the inhibition of these onco-adaptor proteins abrogates HGF triggered responses such as proliferation, migration, and invasion. Expanding on these previous studies, herein we investigated the role of mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK) pathways in the HGF-dependent and HGF-independent NT2D1 cells biological responses. To inhibit MAPK/ERK pathways we chose a pharmacological approach, by using U0126 inhibitor, and we analyzed cell proliferation, collective migration, and chemotaxis. The administration of U0126 together with HGF reverts the HGF-dependent activation of cell proliferation but, surprisingly, does not exert the same effect on NT2D1 cell migration. In addition, we found that the use of U0126 alone significantly promotes the acquisition of NT2D1 «migrating phenotype», while collective migration of NT2D1 cells was stimulated. Notably, the inhibition of ERK activation in the absence of HGF stimulation resulted in the activation of the AKT-mediated pathway, and this let us speculate that the paradoxical effects obtained by using U0126, which are the increase of collective migration and the acquisition of partial epithelium–mesenchyme transition (pEMT), are the result of compensatory pathways activation. These data highlight how the specific response to pathway inhibitors, should be investigated in depth before setting up therapy.

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“…Another proposed anticancer mechanism of Met points to the drug-induced modulation of specific mitogenic stimuli, such as insulin, IGFs and related binding proteins, leading to decreased activation of insulin/IGF receptors, and thus, reduced proliferation and progression of tumors dependent on these signaling pathways ( 7 ). The IGFs system has an essential role in the normal development and embryonic migration of PGCs, as well as in the tumorigenic process of these cells, including cisplatin-resistance and metastatic spread of male GCTs, often characterized by sustained activity of the IGF1R signaling pathway ( 55 ). In this context, the potential of Met as an effective adjuvant therapy reverting cisplatin-resistance in male GCTs, has recently been reported ( 56 ).…”

Section: Discussionmentioning

confidence: 99%

The anticancer effects of Metformin in the male germ tumor SEM-1 cell line are mediated by HMGA1

et al. 2022

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IntroductionGerm cell tumors (GCTs) are the most common type of cancer in young men. These tumors usually originate from the testis, but they can occasionally develop from extragonadal sites probably due to primordial germ cells (PGCs) migration errors. Cisplatin-based chemotherapy is usually effective for male GCTs, but the risk of toxicity is high and new therapeutic strategies are needed. Although Metformin (Met) has been widely studied as a potential cancer treatment over the past decades, there is limited evidence to support its use in treating male GCTs. Additionally, the mechanism by which it acts on tumor cells is still not entirely understood.MethodsSEM-1 cells, a newly established human cell line of extragonadal origin, were treated with Met. Cell viability was studied by MTT assay, while cell migration and invasion were studied by the wound healing assay and the transwell assay, respectively. The effect of Met on 3D spheroid formation was determined by seeding SEM-1 cells in appropriate cell suspension culture conditions, and cell cycle was characterized by flow cytometry. Factors involved in PGCs migration and GCT invasion, such as IGFBP1, IGF1R, MMP-11 and c-Kit, together with cyclin D1 (a key regulator of cell cycle progression), and the upstream factor, HMGA1, were determined by immunoblots.ResultsTreatment of SEM-1 cells with Met resulted in a potent and dose-dependent reduction of cell proliferation, as evidenced by decreased nuclear abundance of cyclin D1 and cell cycle arrest in G1 phase. Also, Met prevented the formation of 3D spheroids, and blocked cell migration and invasion by reducing the expression of IGFBP1, IGF1R and MMP-11. Both, IGFBP1 and MMP-11 are under control of HMGA1, a chromatin-associated protein that is involved in the regulation of important oncogenic, metabolic and embryological processes. Intriguingly, an early reduction in the nuclear abundance of HMGA1 occurred in SEM-1 cells treated with Met.ConclusionsOur results document the antiproliferative and antimigratory effects of Met in SEM-1 cells, providing new insights into the potential treatments for male GCTs. The anticancer properties of Met in SEM-1 cells are likely related to its ability to interfere with HMGA1 and downstream targets, including cyclin D1, the IGFs system, and MMP-11.

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IGF signalling in germ cells and testicular germ cell tumours: roles and therapeutic approaches

Cited by 8 publications

References 106 publications

The PI3K/AKT Pathway Is Activated by HGF in NT2D1 Non-Seminoma Cells and Has a Role in the Modulation of Their Malignant Behavior

The PI3K/AKT Pathway Is Activated by HGF in NT2D1 Non-Seminoma Cells and Has a Role in the Modulation of Their Malignant Behavior

ERK Signaling Pathway Is Constitutively Active in NT2D1 Non-Seminoma Cells and Its Inhibition Impairs Basal and HGF-Activated Cell Proliferation

The anticancer effects of Metformin in the male germ tumor SEM-1 cell line are mediated by HMGA1

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