Insights into the role of IL-32 in cancer

Sloot, Yvette J E; Smit, Johannes W. A.; Joosten, Leo A. B.; Netea‐Maier, Romana T.

doi:10.1016/j.smim.2018.03.004

Cited by 61 publications

(70 citation statements)

References 74 publications

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“…Thus, via an indirect route, TAMs may influence adaptive anti-tumour immune responses in TC as well. Interestingly, in the present study we found that TAM-derived TNFα induced IL-32 expression in TC cells and IL-32 expression in tumour cells is known to affect adaptive immune responses in several other solid cancers [9]. In vitro studies and animal models of different solid cancer types, including colon and prostate cancer, have revealed that IL-32β can stimulate the adaptive anti-tumour response by inducing NK cytotoxicity, thereby increasing T cell infiltration and stimulating a cytotoxic T cell response [12,31,32].…”

Section: Discussionsupporting

confidence: 45%

“…In contrast, other reports indicated that IL-32 may have a more pro-tumorigenic function, especially with respect to mediating invasion and migration in lung, breast and gastric cancers and in osteosarcoma, effects that have not been linked to a specific isoform [13][14][15][16]. Thus, IL-32 seems to exert opposite effects in the context of different cell-and cancer types, which also depends on which isoform is present [9]. The role of IL-32 in non-medullary, differentiated thyroid cancer (TC) has only scarcely been investigated.…”

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confidence: 82%

“…Since its discovery, nine different isoforms of IL-32 have been identified, all resulting from alternative splicing of IL-32γ pre-mRNA [2,3]. IL-32 has been linked to the pathogenesis of several diseases, including inflammatory diseases, cardiovascular diseases and cancer [3][4][5][6][7][8][9]. Especially in the context of cancer, the role of IL-32 seems ambiguous.…”

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confidence: 99%

“…Especially in the context of cancer, the role of IL-32 seems ambiguous. Several reports point towards a tumour suppressive role for IL-32 [9][10][11][12], with IL-32β and IL-32γ being associated with inhibition of melanoma and colon cancer cell growth [10] and with induction of an antitumour immune response in prostate and colon cancer cells [12]. In contrast, other reports indicated that IL-32 may have a more pro-tumorigenic function, especially with respect to mediating invasion and migration in lung, breast and gastric cancers and in osteosarcoma, effects that have not been linked to a specific isoform [13][14][15][16].…”

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confidence: 99%

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Interplay between thyroid cancer cells and macrophages: effects on IL-32 mediated cell death and thyroid cancer cell migration

et al. 2019

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Purpose Interleukin 32 (IL-32) is a pro-inflammatory cytokine of which different isoforms have been identified. Recently, IL-32 has been shown to act as a potent inducer of cell migration in several types of cancer. Although previous research showed that IL-32 is expressed in differentiated thyroid cancer (TC) cells, the role of IL-32 in TC cell migration has not been investigated. Furthermore, tumour-associated macrophages (TAMs) may play a facilitating role in cancer cell migration. The aim of this study was to explore whether the interaction between TC cells and TAMs results in increased expression of IL-32 in TC cells and to investigate whether this affects TC cell migration. Methods TPC-1 cells were co-culture with TC-induced or naive macrophages. Next, transcriptome analysis on TPC-1 cells was performed and supernatants were used for stimulation of TPC-1 cells. IL-32β and IL-32γ were exogenously overexpressed in TPC-1 cells using transient transfection, after which an in vitro gap closure assay was performed to assess cell migration, and the expression of migratory factors was assessed using RT-qPCR. Results We found that TC-induced macrophages induced IL-32 expression in TC cells and that TAM-derived TNFα was the main inducer of IL-32β expression in TC cells. Overexpression of IL-32β and IL-32γ did not affect TC cell migration, but increased cell death. Finally, we found that IL-32β overexpression led to increased mRNA expression of the pro-survival cytokine IL-8, while the expression of other migratory factors was not affected. Conclusions From our data, we conclude that TAM-derived TNFα induces IL-32β in TC cells. Although IL-32β does not affect TC cell migration, alternative splicing of IL-32 towards the IL-32β isoform may be beneficial for TC cell survival through induction of the pro-survival cytokine IL-8.

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Section: Discussionsupporting

confidence: 45%

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confidence: 82%

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confidence: 99%

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Interplay between thyroid cancer cells and macrophages: effects on IL-32 mediated cell death and thyroid cancer cell migration

et al. 2019

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“…3c). Many of the upregulated genes encode secreted proteins known to remodel the tumor microenvironment, including factors that promote reorganization of the extracellular matrix, such as SERPINE1, MMP2 and CTGF 14,15,33 , immunosuppressive cytokines such as CXCL8, CCL2 and IL32 34,35 , as well as ligands that promote cell-to-cell communication such as WNT3, WNT5B and BMP8B 36,37 (Fig. 3c, Extended Data Fig.…”

Section: Discussionmentioning

confidence: 99%

Age-induced methylmalonic acid accumulation promotes tumor progression and aggressiveness

Gomes

Ilter

Low

et al. 2020

Preprint

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From age 65 onwards, the risk of cancer incidence and associated mortality is substantially higher 1-3 . Nonetheless, our understanding of the complex relationship between age and cancer is still in its infancy 4 . For decades, the link has largely been attributed to increased exposure time to mutagens in older individuals. However, this view does not account for the wellestablished role of diet, exercise and small molecules that target the pace of metabolic aging [5][6][7][8] . Here, we show that metabolic alterations that occur with age can render a systemic environment favorable to progression and aggressiveness of tumors. Specifically, we show that methylmalonic acid (MMA), a by-product of propionate metabolism, is significantly up-regulated in the serum of older people, and functions as a mediator of tumor progression. We traced this to the induction of SOX4 and a consequent transcriptional reprogramming that can endow cancer cells with aggressive properties. Thus, accumulation of MMA represents a novel link between aging and cancer progression, implicating MMA as a novel therapeutic target for advanced carcinomas.It has long been known that age is one of the main risk factors for cancer incidence [9][10][11] . How it contributes to cancer progression, however, is not well understood 2,3,12 . Considering the growing body of evidence demonstrating that cancer cell-extrinsic factors are key in modulating tumor progression, we hypothesized that aging produces a systemic environment that supports tumor progression and development of aggressive properties. To test this hypothesis, we cultured A549 non-small cell lung cancer (NSCLC) and HCC1806 triple negative breast cancer (TNBC) cells in 10% human serum from 30 young (age ≤ 30) and 30 old (age ≥ 60) individuals with no diagnosed disease ( Fig. 1a; Extended Data Table 1). While the majority of cells treated with young donor sera maintained their epithelial morphology (25 out of 30), cells treated with 25 out of the 30 old donor sera became mesenchymal, losing polarity and displaying a spindle-shaped morphology (Extended Data Fig. 1-3). These phenotypes were independent of donor ethnicity, and resembled epithelial-to-mesenchymal transition (EMT), a developmental process that during cancer pathogenesis can confer cells the cellular plasticity necessary to acquire proaggressive and pro-metastatic properties 13 . Cells cultured in the presence of sera from aged donors displayed a pronounced loss of the epithelial marker E-cadherin and gain of the mesenchymal markers fibronectin and vimentin 13 , in addition to increased expression of SERPINE1 and MMP2 14,15 -proteins highly associated with aggressive phenotypes (Fig. 1b, Extended Data Fig. 4a, b). Moreover, the aged sera promoted resistance to two distinct and widely used chemotherapeutic drugs, carboplatin and paclitaxel (Fig. 1c, Extended Data Fig. 4c). Compelled by these observations, we questioned if the cells treated with the old donor sera would also display heightened metastatic potential. We treated MDA-MB-2...

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Modulatory effects of point‐mutated IL‐32θ (A94V) on tumor progression in triple‐negative breast cancer cells

Park,

Kim

et al. 2023

BioFactors

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Breast cancer is a frequently diagnosed cancer and the leading cause of death among women worldwide. Tumor‐associated macrophages stimulate cytokines and chemokines, which induce angiogenesis, metastasis, proliferation, and tumor‐infiltrating immune cells. Although interleukin‐32 (IL‐32) has been implicated in the development and modulation of several cancers, its function in breast cancer remains elusive. Mutation of interleukin‐32θ (IL‐32θ) in the tissues of patients with breast cancer was detected by Sanger sequencing. RT‐qPCR was used to detect the mRNA levels of inflammatory cytokines, chemokines, and mediators. The secreted proteins were detected using respective enzyme‐linked immunosorbent assays. Evaluation of the inhibitory effect of mutant IL‐32θ on proliferation, migration, epithelial–mesenchymal transition (EMT), and cell cycle arrest in breast cancer cells was conducted using MTS assays, migration assays, and Western blotting. A point mutation (281C>T, Ala94Val) was detected in IL‐32θ in both breast tumors and adjacent normal tissues, which suppressed the expression of pro‐inflammatory factors, EMT factors, and cell cycle related factors. Mutated IL‐32θ inhibited the expression of inflammatory factors by regulating the NF‐κB pathway. Furthermore, mutated IL‐32θ suppressed EMT markers and cell cycle related factors through the FAK/PI3K/AKT pathway. It was inferred that mutated IL‐32θ modulates breast cancer progression. Mutated IL‐32θ (A94V) inhibited inflammation, EMT, and proliferation in breast cancer by regulating the NF‐κB (p65/p50) and FAK‐PI3K‐GSK3 pathways.

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Insights into the role of IL-32 in cancer

Cited by 61 publications

References 74 publications

Interplay between thyroid cancer cells and macrophages: effects on IL-32 mediated cell death and thyroid cancer cell migration

Interplay between thyroid cancer cells and macrophages: effects on IL-32 mediated cell death and thyroid cancer cell migration

Age-induced methylmalonic acid accumulation promotes tumor progression and aggressiveness

Modulatory effects of point‐mutated IL‐32θ (A94V) on tumor progression in triple‐negative breast cancer cells

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