Interleukin-6 at the Host-Tumor Interface: STAT3 in Biomolecular Condensates in Cancer Cells
It was recognized over 30 years ago that the polyfunctional cytokine interleukin-6 (IL-6) was an almost invariant presence at the host-tumor interface. The IL-6 in the tumor microenvironment was produced either by the cancer cell or by host stromal cells, or by tumor-infiltrating immune cells, or al...
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MDPI AG
2022-03-01
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| Online Access: | https://www.mdpi.com/2073-4409/11/7/1164 |
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| author | Pravin B. Sehgal |
| author_facet | Pravin B. Sehgal |
| author_sort | Pravin B. Sehgal |
| collection | DOAJ |
| description | It was recognized over 30 years ago that the polyfunctional cytokine interleukin-6 (IL-6) was an almost invariant presence at the host-tumor interface. The IL-6 in the tumor microenvironment was produced either by the cancer cell or by host stromal cells, or by tumor-infiltrating immune cells, or all of them. IL-6 effects in this context included local changes in tumor cell-cell and cell-substrate adhesion, enhanced motility, epithelial to mesenchymal transformation (EMT), and changes in cell proliferation rates in both solid tumors as well as hematologic dyscrasias. Locally produced IL-6 enhanced cancer-targeting functions of tumor-infiltrating macrophages and immune cells. Additionally, the sex-biased phenotype of certain cancers [e.g., hepatocellular carcinoma (HCC) which is 3-5-fold more common in men] was related to the inhibition of macrophage-derived IL-6 production by estradiol-17β (E2). In many circumstances, locally produced IL-6 reached the peripheral circulation and elicited systemic effects such as cachexia and paraneoplastic syndrome (including fever, increased erythrocyte sedimentation rate, increased levels of C-reactive protein in serum, hypoalbuminemia). This review highlights the EMT produced by IL-6 in cancer cells, as well as mechanisms underlying sex bias in HCC, enhanced IL-6 expression in cancer cells resulting from mutations in p53, consequent alterations in STAT3 transcriptional signaling, and the newer understanding of STAT3 nuclear bodies in the cancer cell as phase-separated biomolecular condensates and membraneless organelles (MLOs). Moreover, the perplexing issue of discrepant measurements of IL-6 in human circulation using different assays, especially in patients undergoing immunotherapy, is discussed. Additionally, the paradoxical chaperone (enhancing) effect of anti-IL-6 “neutralizing” antibodies on IL-6 in vivo and consequent limitations of immunotherapy using anti-IL-6 mAb is considered. |
| first_indexed | 2024-03-09T12:01:12Z |
| format | Article |
| id | doaj.art-ed38f61b9a534123a49f8a2522cc9443 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T12:01:12Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj.art-ed38f61b9a534123a49f8a2522cc94432023-11-30T23:04:21ZengMDPI AGCells2073-44092022-03-01117116410.3390/cells11071164Interleukin-6 at the Host-Tumor Interface: STAT3 in Biomolecular Condensates in Cancer CellsPravin B. Sehgal0Department of Cell Biology & Anatomy, New York Medical College, Valhalla, NY 10595, USAIt was recognized over 30 years ago that the polyfunctional cytokine interleukin-6 (IL-6) was an almost invariant presence at the host-tumor interface. The IL-6 in the tumor microenvironment was produced either by the cancer cell or by host stromal cells, or by tumor-infiltrating immune cells, or all of them. IL-6 effects in this context included local changes in tumor cell-cell and cell-substrate adhesion, enhanced motility, epithelial to mesenchymal transformation (EMT), and changes in cell proliferation rates in both solid tumors as well as hematologic dyscrasias. Locally produced IL-6 enhanced cancer-targeting functions of tumor-infiltrating macrophages and immune cells. Additionally, the sex-biased phenotype of certain cancers [e.g., hepatocellular carcinoma (HCC) which is 3-5-fold more common in men] was related to the inhibition of macrophage-derived IL-6 production by estradiol-17β (E2). In many circumstances, locally produced IL-6 reached the peripheral circulation and elicited systemic effects such as cachexia and paraneoplastic syndrome (including fever, increased erythrocyte sedimentation rate, increased levels of C-reactive protein in serum, hypoalbuminemia). This review highlights the EMT produced by IL-6 in cancer cells, as well as mechanisms underlying sex bias in HCC, enhanced IL-6 expression in cancer cells resulting from mutations in p53, consequent alterations in STAT3 transcriptional signaling, and the newer understanding of STAT3 nuclear bodies in the cancer cell as phase-separated biomolecular condensates and membraneless organelles (MLOs). Moreover, the perplexing issue of discrepant measurements of IL-6 in human circulation using different assays, especially in patients undergoing immunotherapy, is discussed. Additionally, the paradoxical chaperone (enhancing) effect of anti-IL-6 “neutralizing” antibodies on IL-6 in vivo and consequent limitations of immunotherapy using anti-IL-6 mAb is considered.https://www.mdpi.com/2073-4409/11/7/1164cytokinesinterleukin-6 (IL-6)cancer cellsstromal cellsmacrophagesepithelial to mesenchymal transformation (EMT) |
| spellingShingle | Pravin B. Sehgal Interleukin-6 at the Host-Tumor Interface: STAT3 in Biomolecular Condensates in Cancer Cells Cells cytokines interleukin-6 (IL-6) cancer cells stromal cells macrophages epithelial to mesenchymal transformation (EMT) |
| title | Interleukin-6 at the Host-Tumor Interface: STAT3 in Biomolecular Condensates in Cancer Cells |
| title_full | Interleukin-6 at the Host-Tumor Interface: STAT3 in Biomolecular Condensates in Cancer Cells |
| title_fullStr | Interleukin-6 at the Host-Tumor Interface: STAT3 in Biomolecular Condensates in Cancer Cells |
| title_full_unstemmed | Interleukin-6 at the Host-Tumor Interface: STAT3 in Biomolecular Condensates in Cancer Cells |
| title_short | Interleukin-6 at the Host-Tumor Interface: STAT3 in Biomolecular Condensates in Cancer Cells |
| title_sort | interleukin 6 at the host tumor interface stat3 in biomolecular condensates in cancer cells |
| topic | cytokines interleukin-6 (IL-6) cancer cells stromal cells macrophages epithelial to mesenchymal transformation (EMT) |
| url | https://www.mdpi.com/2073-4409/11/7/1164 |
| work_keys_str_mv | AT pravinbsehgal interleukin6atthehosttumorinterfacestat3inbiomolecularcondensatesincancercells |