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Inflammation Amplifier, a New Paradigm in Cancer Biology
Abstract
Tumor-associated inflammation can induce various molecules expressed from the tumors themselves or surrounding cells to create a microenvironment that potentially promotes cancer development. Inflammation, particularly chronic inflammation, is often linked to cancer development, even though its evolutionary role should impair nonself objects including tumors. The inflammation amplifier, a hyperinducer of chemokines in nonimmune cells, is the principal machinery for inflammation and is activated by the simultaneous stimulation of NF-κB and STAT3. We have redefined inflammation as local activation of the inflammation amplifier, which causes an accumulation of various immune cells followed by dysregulation of local homeostasis. Genes related to the inflammation amplifier have been genetically associated with various human inflammatory diseases. Here, we describe how cancer-associated genes, including interleukin (IL)-6, Ptgs2, ErbB1, Gas1, Serpine1, cMyc, and Vegf-α, are strongly enriched in genes related to the amplifier. The inflammation amplifier is activated by the stimulation of cytokines, such as TNF-α, IL-17, and IL-6, resulting in the subsequent expression of various target genes for chemokines and tumor-related genes like BCL2L11, CPNE7, FAS, HIF1-α, IL-1RAP, and SOD2. Thus, we conclude that inflammation does indeed associate with the development of cancer. The identified genes associated with the inflammation amplifier may thus make potential therapeutic targets of can…
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“It too plays a key role in inflammatory diseases including cytokine storm syndromes, autoimmune diseases and cancer (10, 11, 15, 41, 66–68)”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [11]
In the citing paper
“Among them, IL-6 is a major player in chronic inflammatory diseases, autoimmune diseases, cancer and cytokine storm (1, 3, 10–26).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [11]
In the citing paper
“Moreover, the IL-6 Amp is related with various types of cancer, including hematologic malignancies, tumors in lung, and colorectal/intestinal, urinary/bladder/vulvar, breast, stomach and liver cancers (11).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [11]
In the citing paper
“Furthermore, many cancer-associated genes were identified as regulators or target genes of the IL-6 Amp (11).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [11]
In the citing paper
“Target molecules of the IL-6 Amp include EGFR, c-Myc, Pim1, VEGFα, hypoxia-inducible factor 1-alpha (HIF1-α), MMPs and many pro-inflammatory cytokines and growth factors involved in cell survival, proliferation, angiogenesis and metastasis (Fig. 3) (10, 11).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [11]
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“Further details about the inflammation amplifier can be found in other review articles (69, 76).”
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BackgroundBmi1 Regulates IκBα Degradation via Association with the SCF Complex
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“We previously found that other cancer-associated genes are enriched in inflammation amplifier activation (42), suggesting that inflammation mediated by the NF-kB signal via the amplifier enables CSCs and/or cancer cells to escape the immune system and trigger their survival by developing inflammation.”
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“As a molecular mechanism for inflammation development, we previously discovered the inflammation amplifier, which is a chemokine hyperproduction mechanism operated in nonimmune cells such as fibroblasts and endothelial cells (5, 6).”
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“…a Ca 2 + - dependent, phospholipid-binding protein that is highly elevated in certain T cells and has been implicated as inflammation amplifier, 53 as well as Il34 (Figure 4C,F and Table S5), the gene for interleukin-34, the alternate ligand of the CSF-1 receptor CSF1R, with important…”
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“Inflammatory physiological changes, such as oxidative stress, exert downstream genotoxic effects (54).”
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Self-citationRETRACTION: STAT3 Regulates Steady-State Expression of Synaptopodin in Cultured Mouse Podocytes
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“Within the proinflammatory milieu in which one expects STAT3 activation (Dai et al., 2013; Atsumi et al., 2014), increased stiffness might function to counteract increased intraglomerular pressures in early stages of the disease process (Anderson andBrenner, 1986), or could function to prevent…”
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“We named this synergistic mechanism in non-immune cells the “inflammation amplifier,” because the high levels of pro-inflammatory mediators including chemokines induced in non-immune cells can recruit many kinds of immune cells and promote more inflammation.(37,38) Consistent with the concept of the inflammation ampli…”
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“Recently, the relationship between inflammation and cancer has been widely investigated and inflammation has been defined as the major hallmark of cancer [4–6].”
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“We have reported that the IL-6 amplifier is a molecular mechanism for inflammation induction in various inflammatory diseases 22,23 .”
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“Activation of NF-kB and STAT is associated with cancer associated inflammation by secreting cytokines that stimulate tumor survival and clonogenic capacity (49, 54).”
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“Another study demonstrated that BCL2L11 is an inflammation amplifier [24].”
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“The inflammation amplifier is activated by the stimulation of cytokines, such as TNF-α, IL-17, and noradrenaline, resulting in the subsequent expression of various target genes for chemokine [18].”
BackgroundKato, S., Hikita, H., Tsukamoto, O., Sato, K., Kamizono, K., Sasaki, Y., Fukumoto, K., Myojin, Y., Murai, K., Tahata, Y., et al. (2026) · Gastroenterology · doi:10.1053/j.gastro.2025.11.014 · Cited by 5
Cicinelli, E., Nicolì, P., Vimercati, A., Cicinelli, R., Marinaccio, M., Matteo, M., de Ziegler, D., & Vitagliano, A. (2025) · International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics · doi:10.1002/ijgo.70115 · Cited by 4
“Dysregulation of TNF 𝛼 production has been implicated in several inflammatory processes and other human diseases, such us inflammatory bowel diseases and cancer, 35 respectively.”
Diterpenoids from Euphorbia lathyris L.: a comprehensive review update
Wang, X., Xu, Y., Wang, Y.-L., Lin, F., Li, H., & Chen, L.-X. (2025) · Phytochemistry Reviews · doi:10.1007/s11101-025-10100-1 · Cited by 4
“Inflammation is a natural response of the body to pathogens and injury, but excessive inflammatory responses can lead to tissue damage and dysfunction, which in turn promotes the development of chronic diseases and cancer (Atsumi et al. 2014; Maccallini et al. 2017; Medzhitov 2008).”
Tanda, M., Yamamoto, K., Hori, T., Nishiguchi, H., Yagi, M., Shimizu, M., Konishi, T., Ozaki, T., YOSHIOKA, N., TACHIHARA, M. Y., et al. (2023) · Anticancer Research · doi:10.21873/anticanres.16331 · Cited by 3
The unfolded protein response, inflammation, oscillators, and disease: a systems biology approach
Rangel‐Aldao, R. (2015) · Endoplasmic Reticulum Stress in Diseases · doi:10.1515/ersc-2015-0003 · Cited by 6
“Thus, as with the other NCDs mentioned previously, cancer exhibits a vicious circle whereby locally initiated events of cell-cell communication of stressed cells may lead to the amplification of cancer-initiated inflammation [40].”
BackgroundInflammation-induced cell-secreted migrasome promotes IL-6 expression in the recipient cells.
Saito, S., Yoshikawa, K., Tanaka, M., Murakami, M., & Okochi, M. (2026) · Biomaterials Advances · doi:10.1016/j.bioadv.2026.214793 · Cited by 3
Self-citationLiu, J.-J., Wang, L.-Z., Duan, Y.-T., Li, R.-T., Liu, D., & Li, H.-M. (2025) · Archives of pharmacal research · doi:10.1007/s12272-025-01571-z · Cited by 3
“However, an excessive inflammatory response can injure tissues and organs, leading to various diseases, such as cancer, rheumatoid arthritis, type 2 diabetes, bronchitis, and gynecological diseases (Medzhitov 2008; Atsumi et al. 2014; Nasef et al. 2017).”
Yu, C., Xu, J., Xu, S., Huang, Y., Tang, L., Zeng, X., Yu, T., Chen, W., & Sun, Z. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2023.1275913 · Cited by 5
“Chronic in fl ammation characterized by sustained immune activation is associated with promoting the occurrence, growth, and progression of BC (10 – 12).”
BackgroundAlmeida, T. C. D. C., Zatta, S. M., Paiva, L. D. S., de Carvalho, L. E. D., Schoueri, J., de Abreu, L. D., Fonseca, F., & Adami, F. (2022) · Mediators of Inflammation · doi:10.1155/2022/1350813 · Cited by 3
Zangeneh, F., Naghizadeh, M., & Jafarabadi, M. (2015) · doi:10.9734/arrb/2015/19397 · Cited by 3
“[47] in 2014 have redefined inflammation as local activation of the inflammation amplifier, which causes an accumulation of various immune cells followed by deregulation of local homeostasis.”
BackgroundPathological mechanisms of cold and mechanical stress in modulating cancer progression
Hou, Y., Yang, X., He, L., & Meng, H. (2024) · Human Cell · doi:10.1007/s13577-024-01049-y · Cited by 3
“In the TME, especially the T cells signal transduction in immune cells, over-activation of the NF-kB and STAT3 signaling pathways also makes rise of inflammatory cytokines, such as IL-1, IL-6, and MMP9, and strengthened carcinogenesis [74, 75]. c. Tumor and vascular rapid reproduction.”
Value of Cytokine Expression in Early Diagnosis and Prognosis of Tumor Metastasis
Li, T.-W., Liu, M.-L., Dai, H.-R., Li, X., Liao, J., Zheng, Z., Pan, Y.-H., Liu, Y., & Fang, S. (2022) · Journal of Oncology · doi:10.1155/2022/8112190 · Cited by 2
Cavalcoli, F., Pusceddu, S., Zilli, A., Tamagno, G., Femia, D., Prinzi, N., Travers, J., Consonni, D., Ciafardini, C., Conte, D., et al. (2019) · Scandinavian Journal of Gastroenterology · doi:10.1080/00365521.2019.1656773 · Cited by 2
“Inflammation is thought to be a common and plausible mechanism through which risk factors may predispose to cancer development and consequently may represent an important therapeutic target [9,10].”
BackgroundKamimura, D., Arima, Y., Štofková, A., Nishikawa, N., Higuchi, K., Ohki, T., & Murakami, M. (2016) · InTech eBooks · doi:10.5772/62938 · Cited by 1
“Since chemokines can recruit immune cells and promote inflammation, we named this synergistic mechanism in nonimmune cells the “inflammation amplifier” [64, 65].”
BackgroundSelf-citationGenomic Analysis Reveals Strong Signatures of Selection in Guangxi Three-Yellow Chicken in China
Liao, Y., Sun, J., Huang, Y., Wei, F., Mo, G., Zellmer, L., & Liao, D. J. (2020) · Journal of World s Poultry Research · doi:10.36380/jwpr.2020.48 · Cited by 6
“As a putative tumor suppressor gene (Del et al., 1992; Del et al., 1994; Atsumi et al., 2014), Growth arrest-specific 1(GAS1) inhibits cell replication by blocking the entry into the S”
BackgroundOMICfpp: a fuzzy approach for paired RNA-Seq counts
Berral-González, A., Riffo‐Campos, Á. L., & Ayala, G. (2019) · BMC Genomics · doi:10.1186/s12864-019-5496-5 · Cited by 1
Gateway Reflex: A Neuro-Immune Crosstalk for Organ-Specific Disease Development
Kamimura, D., Tanaka, Y., Ohki, T., & Murakami, M. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.77112 · Cited by 1
Self-citationOkuyan, H., Terzi, M., Güneri, C. Ö., & Urhan-Kucuk, M. (2018) · Konuralp Tip Dergisi · doi:10.18521/ktd.398669 · Cited by 1
“In the studies including up to date, the relation between cancer and inflammation has been intensely investigated and it is reported that inflammation is an important compound of the cancer (3-7).”
BackgroundAnalyses of the Interleukin32 Transcript Variants in Breast Cancer Cell Lines
Burrell, K., & Player, A. N. (2016) · American Journal of Immunology · doi:10.3844/ajisp.2016.83.90
“…variants and protein sequences were analyzed using NCBI tools including the Basic Local Alignment Search Tool (BLAST; https://blast.ncbi.nlm.nih.gov/Blast.cgi), University of California Santa Cruz Genome Brower (UCSC Genome Browser; https://genome.ucsc.edu/) and the Multalin program (Corpet, 1988).”
MethodPain is an inducer for relapse in multiple sclerosis models through a regional neural signal
Arima, Y., Higuchi, K., Nishikawa, N., Štofková, A., Ohki, T., Kamimura, D., & Murakami, M. (2015) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12250 · Cited by 2
Self-citationImmune cell gateways in the central nervous system regulated by regional neural stimulations
Kamimura, D., Štofková, A., Nishikawa, N., Atsumi, T., Arima, Y., & Murakami, M. (2015) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12198 · Cited by 1
“including MS and cancer, were significantly enriched in inflammation amplifier-related genes.(49,50) In addition, genes genetically linked with neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis, were also significantly enriched in the candidate genes, sugges…”
BackgroundSelf-citationColitis-associated colorectal carcinogenesis: molecular mechanisms and therapeutic potential
Lu, Y., Wang, X., Yin, C., Wang, J., Guo, S., Wang, Z., Zhou, J., Cui, M., Cheng, X., Zhang, L., et al. (2026) · Molecular Biomedicine · doi:10.1186/s43556-026-00623-0
“It is important to note that chemokines can serve both as downstream targets of the NF-κB signaling pathway and as indirect amplifiers of it [137, 138].”
Tanaka, Y., Wang, Y., Tanaka, H., Hojyo, S., Kamiya, N., Murakami, K., & Murakami, M. (2026) · Discover Nano · doi:10.1186/s11671-026-04830-0
Self-citationFive undescribed compounds isolated from Gerbera delavayi with their anti-inflammatory activity.
Jiang, L., Wang, Y., Ran, Z., Lu, D.-Y., Li, R., Sun, J., Huang, Y., Ma, X., & Li, Y.-J. (2026) · Phytochemistry · doi:10.1016/j.phytochem.2026.115013
Silva, A. G., Pereira, E., Almeida, V. H., Pinto, L. D. M., Souza, J. L., Tilli, T. M., Coutinho‐Silva, R., Medei, E. H., König, S., & Monteiro, R. Q. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27052230
“In 1863, Rudolf Virchow hypothesized that chronic inflammation could lead to malignant neoplasms, promoting cell proliferation and tumor development [4,5].”
Lv, X.-Y., Ji, L., Cao, W., Xue, Y., Dai, H., & Zhang, S.-Z. (2025) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2025.1657691
Yang, W.-F., Wu, X., Wang, J., Ou, W., & Huang, X. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2025.1584619
“IL-1RAP plays a crucial role in mediating the IL-1 signaling pathway, which is implicated in in fl ammation, cancer, neurological disorders, metabolic diseases, and infectious diseases (28).”
You, T., Peng, K., Yi, J., Du, Y., Jiang, P.-Y., Zeng, D., Wu, J., Liu, J., & Wu, S.-J. (2024) · Shock · doi:10.1097/shk.0000000000002504
“BCL-2-like 11 (BCL2L11, also known as Bim and BAM) is a BH3-only domain-containing protein in BCL-2 family and is a key proapoptotic gene targeted by the inflammation amplifier (20,21).”
Iugai, S., Gushchin, V., King, M., Kovalik, V., Falla-Zúñiga, L. F., Nieroda, C., & Sardi, A. (2024) · Surgical Oncology Insight · doi:10.1016/j.soi.2024.100101
“8,9 Recent studies demonstrated that pseudomyxoma peritonei (PMP) has a unique microenvironment, associated with various pro-inflammatory cytokines, reflecting the role of inflammation in tumor development.”
Higuchi, K., Kamimura, D., Štofková, A., Nishikawa, N., Ohki, T., Arima, Y., & Murakami, M. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-805298-3.00005-0
Self-citation
Metadata
- Authors
- Atsumi, T., Singh, R., Sabharwal, L., Bando, H., Meng, J., Arima, Y., Yamada, M., Harada, M., Jiang, J.-J., Kamimura, D., Ogura, H., Hirano, T., & Murakami, M.
- Affiliations
- Japan Science and Technology Agency (JP)
- ORCID
- Venue
- Cancer Research
- Published
- 2014-01-01
- Volume
- 74
- Issue
- 1
- Pages
- 8-14
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2101899879
- Cited by
- 217
- References
- 0
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 18 · 2023: 13 · 2022: 16 · 2021: 14 · 2020: 12 · 2019: 18 · 2018: 18 · 2017: 20 · 2016: 20 · 2015: 33 · 2014: 14
- FWCI
- 2.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (24790472, 24249028, 26460574, 24390098)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- tumor inflammation, chronic inflammation, carcinogenesis, NF-κB, STAT3, tumor microenvironment, cytokines, interleukin-6, cyclooxygenase-2, EGF receptor, GAS1, SERPINE1, c-Myc, VEGFα, HIF-1α, therapeutic target
- MeSH terms
- Animals, Humans, Inflammation, Neoplasms, Signal Transduction, Tumor Microenvironment
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