Effects of type I interferons on IGF-mediated autocrine/paracrine growth of human neuroendocrine tumor cells

Abstract

We recently demonstrated that interferon (IFN)-β has a more potent antitumor activity than IFN-α in BON cells, a neuroendocrine tumor (NET) cell line. The present study showed the role of type I IFNs in the modulation of the insulin-like growth factor (IGF) system in NETs. BON cells expressed IGF-I, IGF-II, IGF-I receptor, and insulin receptor mRNA. In addition, IGF-I and IGF-II stimulated the proliferation of BON cells and induced an inhibition of DNA fragmentation (apoptosis). As evaluated by quantitative RT-PCR, treatment with IFN-α (100 IU/ml) or IFN-β (100 IU/ml) inhibited the expression of IGF-II mRNA (−42% and −65%, respectively, both P < 0.001), whereas IGF-I receptor mRNA was significantly upregulated by IFN-α (+28%, P < 0.001) and downregulated by IFN-β (−47%, P < 0.001). Immunoreactive IGF-II concentration decreased in the conditioned medium during IFN-α (−16%, P < 0.05) and IFN-β (−69%, P < 0.001) treatment. Additionally, IGF-I receptor bioactivity was reduced (−54%) after IFN-β treatment. Scatchard analysis of 125I-labeled IGF-I binding to cell membrane of BON cells revealed a dramatic suppression of maximum binding capacity only in the presence of IFN-β. Finally, the proapoptotic activity of IFN-β was partially counteracted by the coadministration of IGF-I and IGF-II (both at 50 nM). In conclusion, these data demonstrate that the IGF system has an important role in autocrine/paracrine growth of BON cells. The more potent antitumor activity of IFN-β compared with IFN-α could be explained by several effects on this system: 1) both IFNs inhibit the transcription of IGF-II, but the suppression is significantly higher after IFN-β than IFN-α and 2) only IFN-β inhibits the expression of IGF-I receptor.

Tumor infiltrating T lymphocytes expressing FoxP3, CCR7 or PD-1 predict the outcome of prostate cancer patients subjected to salvage radiotherapy after biochemical relapse

“…9 The same authors also demonstrated the synergistic antiproliferative activity of combined IFN-b and troglitazone treatment on pancreatic cancer cell lines 10 and the antitumor activity of IFNb in human neuroendocrine cancer cells, mainly counteracting the IGF-II autocrine/paracrine growth loop. 11 The current development of cancer immunotherapy and the relative success of immune-check point inhibitors such as Ipilimumab (anti-CTLA-4) and Nivolumab/Pembrolizumab (anti-PD-1) in the treatment of different malignancies has prompted the design of multiple studies aimed to test this kind of treatment also in PC patients. 1,12,13 At this aim, it has already been shown that PC cells can be recognized and killed by activated cytotoxic T lymphocyte (CTL) precursors sensitized to recognize PTHrP-or PSA-derived epitopes in vitro and in vivo.…”

pEGFR-Tyr 845 expression as prognostic factors in oral squamous cell carcinoma

“…Moreover, two cores from different areas approaches for novel treatment strategies, even if the literature characterizes better the role of these markers in neuroendocrine tumors rather than squamous. [53][54][55][56] However, detailed studies will be required for better understanding of the complex mechanism of carcinogenesis relating to OSCCs and to improve chemoradiotherapy through the discovery of new therapeutic markers. Our data lead support to the need of detecting the expression of EGFR and its phosphorylated isoforms in clinical practice and diagnostic management of OSCCs.…”

Estrogen and Insulin Replacement Therapy Modulates the Expression of Insulin‐Like Growth Factor‐I Receptors in the Salivary Glands of Diabetic Mice

“…Thus, this increase and the reciprocal effect between IGF and IGF-R may be an attempt to regulate the cellular metabolism and the cellular glucose transport (Zoidis et al, 2011). These IGF actions can have also relation with autocrine, paracrine, and with endocrine regulatory mechanisms in different tissues (Pavelić et al, 2007;Vitale et al, 2009). Likewise, also the salivary glands are dependent on factors of growth and endocrine, autocrine, and paracrine signals, which regulate the cell division, apoptosis, and histodifferentiation (Jaskoll and Melnick, 1999).…”