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Interleukin-13 receptor ?2 is a novel marker and potential therapeutic target for human melanoma.

ABSTRACT: Malignant melanoma is one of the untreatable cancers in which conventional therapeutic strategies, including chemotherapy, are hardly effective. Therefore, identification of novel therapeutic targets involved in melanoma progression is urgently needed for developing effective therapeutic methods. Overexpression of interleukin-13 receptor ?2 (IL13R?2) is observed in several cancer types including glioma and pancreatic cancer. Although IL13R?2 is implicated in the progression of various types of cancer, its expression and roles in the malignant melanoma have not yet been elucidated. In the present study, we showed that IL13R?2 was expressed in approximately 7.5% melanoma patients. While IL13R?2 expression in human melanoma cells decreased their proliferation in vitro, it promoted in vivo tumour growth and angiogenesis in melanoma xenograft mouse model. We also found that the expression of amphiregulin, a member of the epidermal growth factor (EGF) family, was correlated with IL13R?2 expression in cultured melanoma cells, xenograft tumour tissues and melanoma clinical samples. Furthermore, expression of amphiregulin promoted tumour growth, implicating causal relationship between the expression of IL13R?2 and amphiregulin. These results suggest that IL13R?2 enhances tumorigenicity by inducing angiogenesis in malignant melanoma, and serves as a potential therapeutic target of malignant melanoma.

SUBMITTER: Okamoto H

PROVIDER: S-EPMC6362032 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Interleukin-13 receptor α2 is a novel marker and potential therapeutic target for human melanoma.

Okamoto Hayato H Yoshimatsu Yasuhiro Y Tomizawa Taishi T Kunita Akiko A Takayama Rina R Morikawa Teppei T Komura Daisuke D Takahashi Kazuki K Oshima Tsukasa T Sato Moegi M Komai Mao M Podyma-Inoue Katarzyna A KA Uchida Hiroaki H Hamada Hirofumi H Fujiu Katsuhito K Ishikawa Shumpei S Fukayama Masashi M Fukuhara Takeshi T Watabe Tetsuro T

Scientific reports 20190204 1

Malignant melanoma is one of the untreatable cancers in which conventional therapeutic strategies, including chemotherapy, are hardly effective. Therefore, identification of novel therapeutic targets involved in melanoma progression is urgently needed for developing effective therapeutic methods. Overexpression of interleukin-13 receptor α2 (IL13Rα2) is observed in several cancer types including glioma and pancreatic cancer. Although IL13Rα2 is implicated in the progression of various types of c ...[more]

PMID: 30718742

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Project description:INTRODUCTION:Interleukin-6 (IL-6) is an important growth factor for estrogen receptor-? (ER?)-positive breast cancer, and elevated serum IL-6 is associated with poor prognosis. METHODS:The role of the phosphorylated signal transducer and activator of transcription 3 pathway was investigated in ER?-positive breast cancer. A panel of cell lines was treated with exogenous IL-6. An IL-6 specific gene signature was generated by profiling ten ER?-positive breast cancer cell lines alone or following treatment with 10 ng/mL recombinant IL-6 or human marrow stromal cell-conditioned media, with or without siltuximab (a neutralizing anti-IL-6 antibody) and grown in three-dimensional tumor microenvironment-aligned cultures for 4 days, 5 days, or 6 days. The established IL-6 signature was validated against 36 human ER?-positive breast tumor samples with matched serum. A comparative MCF-7 xenograft murine model was utilized to determine the role of IL-6 in estrogen-supplemented ER?-positive breast cancer to assess the efficacy of anti-IL-6 therapy in vivo. RESULTS:In eight of nine ER?-positive breast cancer cell lines, recombinant IL-6 increased phosphorylation of tyrosine 705 of STAT3. Differential gene expression analysis identified 17 genes that could be used to determine IL-6 pathway activation by combining their expression intensity into a pathway activation score. The gene signature included a variety of genes involved in immune cell function and migration, cell growth and apoptosis, and the tumor microenvironment. Validation of the IL-6 gene signature in 36 matched human serum and ER?-positive breast tumor samples showed that patients with a high IL-6 pathway activation score were also enriched for elevated serum IL-6 (?10 pg/mL). When human IL-6 was provided in vivo, MCF-7 cells engrafted without the need for estrogen supplementation, and addition of estrogen to IL-6 did not further enhance engraftment. Subsequently, we prophylactically treated mice at MCF-7 engraftment with siltuximab, fulvestrant, or combination therapy. Siltuximab alone was able to blunt MCF-7 engraftment. Similarly, siltuximab alone induced regressions in 90% (9/10) of tumors, which were established in the presence which were established in the presence of hMSC expressing human IL-6 and estrogen. CONCLUSION:Given the established role for IL-6 in ER?-positive breast cancer, these data demonstrate the potential for anti-IL-6 therapeutics in breast cancer.

Project description:BACKGROUND:The development of therapeutic vaccines requires thorough knowledge of potential hazards associated with long-term inactivation of self-proteins. Among potential targets, interleukin 13 (IL-13) merits consideration, as monoclonal antibodies disrupting IL-13 signaling are proving to be exceedingly effective in common conditions such as atopic dermatitis. OBJECTIVE:Given the mass publication of scientific data, an appraisal of safety aspects is challenging. METHODS:We here provide a three-fold approach to survey clinically relevant information on off-target effects, both adverse and beneficial, that may potentially be encountered in patients undergoing long-term IL-13 inactivation. First, we review non-clinical data in vivo and in vitro. Second, we summarize safety data accumulating from patients dosed with anti-IL-13 drugs. Third, we exploit human mutation data as well as emerging large-scale genetic datasets (global exome data from 60,000 patients) to obtain information on any association of IL-13-inactivating genetic variants with disease states. In addition, we: (1) dissect the precise efficacy signals obtained with various drugs targeting IL-13 and/or IL-4, and (2) summarize unintended, but potentially beneficial effects of prolonged IL-13 inactivation on several functional systems. RESULTS:Prolonged repression of IL-13 in several thousand patients so far has not uncovered any non-redundant functions of IL-13 in immune defense. Furthermore, missense mutations in the key genes IL-13, IL-13R?1, IL-13R?2, IL-4, IL-4R? are common, while no case reports have been published on any immune deficiency or increased risk of neoplastic disease associated with such mutations, suggesting that these genes do not harbor non-redundant roles in adult outbred humans. In terms of efficacy, data from clinically used drugs strongly suggest that targeting IL-13 only, as opposed to IL-13 and IL-4, may be effective in eczema while being more selective. Importantly, several lines of evidence suggest that inhibition of IL-13 may in fact harbor potentially beneficial effects on non-targeted systems, including glucose metabolism, hepatic fibrosis, and atherosclerosis, suggesting that respective outcomes should be systematically captured in patients dosed with IL-13 interfering drugs. Collectively, available evidence suggests that IL-13 may fulfill safety requirements required for the target of a therapeutic vaccine.

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Interleukin-13 receptor ?2 is a novel marker and potential therapeutic target for human melanoma.

Publications

Interleukin-13 receptor α2 is a novel marker and potential therapeutic target for human melanoma.

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