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Latest News| New Research Shows Potential to Reverse Cancer Wasting
2024-09-27 09:23:08
On June 1, 2024, in the journal Nature Communications, scientists from Bo Li's research team published an article titled "Area postrema neurons mediate interleukin-6 function in cancer cachexia". The article found that sustained elevation of interleukin-6 can lead to brain dysfunction and ultimately cancer cachexia. The researchers identified the core mechanism of action of peripheral IL-6, which can be significantly weakened by anti-IL-6 antibodies and can enter neurons in the posterior brain area (AP) to activate AP neurons and their related networks. Neutralizing IL-6 in the brain or inhibiting the Il6ra gene encoding IL-6 receptors in AP neurons can reduce cancer cachexia and the overactivity of AP neuronal networks, and prolong their function. The lifespan and mechanism of action were validated using CRISPR/dCas9 technology. Therefore, by elucidating the mechanism of action, AP neurons are key mediators of IL-6 function in the development of cancer cachexia, and IL-6 can serve as a potential therapeutic drug target for cancer cachexia.
BackgroundBACKGROUND
Cancer cachexia
Cancer cachexia is often considered a paraneoplastic syndrome that affects advanced cancer patients, leading to reduced intake and significant weight loss, mainly due to damage to adipose tissue and skeletal muscle. To prevent damage to adipose tissue and skeletal muscle, researchers are searching for relevant cytokines.
TNFα
TNF alpha inhibits the differentiation of adipocytes and skeletal muscle cells, but the correlation between human TNF alpha sources and cancer cachexia is still unclear. There is controversy over whether the level of this cytokine will increase in cancer patients with weight loss, and recent anti TNF alpha antibodies have shown no significant changes. Therefore, it is speculated that TNF alpha may be a promoter, but not enough to promote tissue atrophy, requiring synergistic effects from other tumors or inflammatory factors. Alternatively, one possibility is that there may be more than one cytokine in cancer cachexia, and the lack of significant changes in experimental results may be due to the fact that treating only one cytokine is far from enough, or TNF alpha may only mediate a small portion of the cytokines originating from cancer cachexia. Determine the cancer cachexia caused by elevated levels of TNF α.
Interleukin-6
IL-6 may synergize with TNFαor act alone as a driving factor for systemic inflammation in cancer cachexia. The circulating levels of IL-6 have been shown to be associated with weight loss in cancer patients. However, experiments have shown that only super physiological doses of IL-6 can induce muscle atrophy. The unique targeting of IL-6 may face the same challenges as anti TNF therapy. Experiments have shown that anti-IL-6 antibodies have been validated to improve symptoms such as anorexia, fatigue, and anemia, but have no significant effect on weight loss.
Tumor specific factors
Other mediating factors, such as zinc -α2-glycoprotein (ZAG, also known as lipid mobilization factor) and protein hydrolysis inducing factor (PIF), have selective activity in degrading fat and skeletal muscle, respectively, but their mechanisms of action are not yet clear.
Muscle growth inhibitor and activator
A relatively new factor, namely TGF β family member myostatin, has been studied. In addition to myostatin, other TGF β family members are induced by inflammatory cytokines, and blocking a single TGF β family member (such as myostatin) alone may not be effective.
The mechanism of cytokine research on other cancer cachexia is still unclear and requires further experimental verification.
Interleukin 6 (IL-6)IL-6
Interleukin-6 (IL-6) is an interleukin encoded by the IL-6 gene, which can act as both a pro-inflammatory cytokine and an anti-inflammatory muscle factor. IL-6 is produced by adipocytes. IL-6 stimulates inflammatory and autoimmune processes in many diseases, such as atherosclerosis, Alzheimer's disease, systemic lupus erythematosus, rheumatoid arthritis, etc. IL-6 is a cytokine with multiple effects, as shown in the figure below, which shows the role of IL-6 in inflammation, immunity and diseases.
Figure 1: IL-6 in inflammation, immunity, and disease. (Toshio Tanaka,2014)
The 5 'end of the human IL-6 gene includes binding sites for NF - κ B, specific protein 1 (SP1), nuclear factor IL-6 (NF-IL-6) (also known as CAAT/enhancer binding protein β), activator protein 1 (AP-1), and interferon regulatory factor 1.
Figure 2: Transcriptional and posttranscriptional regulation of IL-6 gene. (Toshio Tanaka,2014)
TechnologyInvovled
Immunohistochemistry
Immunohistochemistry is an immunostaining method. The selective recognition of antigens (proteins) in cells and biological tissues through antibody antigen specific binding is widely used for diagnosing cells in cancer tumors, analyzing biomarkers, and locating protein distribution. The steps include sample preparation (including tissue fixation and sectioning, followed by the use of blocking buffer to reduce non-specific binding of antibodies), incubation with unlabeled primary antibodies (monoclonal or polyclonal antibodies), followed by fluorescence or enzyme-linked immunosorbent assay secondary antibodies, and colorimetric observation after binding to the reporter molecule.
Figure 3: Chromogenic immunohistochemistry: The cell is exposed to a primary antibody (red) that binds to a specific antigen (purple square). The primary antibody binds a secondary (green) antibody that is chemically coupled to an enzyme (blue). The enzyme changes the color of the substrate to a more pigmented one (brown star).(Wikipedia)
Fluorescence in situ hybridization
Fluorescence in situ hybridization (FISH) uses fluorescent probes to bind to specific parts of nucleic acid sequences with high sequence complementarity, for detecting and locating the presence or absence of specific DNA sequences on chromosomes. FISH is commonly used in genetic counseling, medicine, and species identification, and can also be used to detect and locate cells. FISH probes are divided into RNA probes and DNA probes.
Figure 4: Scheme of the principle of the FISH Experiment to localize a gene in the nucleus.(Wikipedia)
CRISPR/dCas9
CRISPR-Cas9 technology delivers Cas9 nucleases, which are complexed with synthetic guide RNA (gRNA), to cells, allowing for the cutting of the cell's genome at desired locations, thereby allowing for the removal of existing genes and/or the addition of new genes in vivo. Using "dead" versions of Cas9 (dCas9) eliminates CRISPR's DNA cutting ability, while preserving its ability to target desirable sequences， Gene editing technology can quickly construct relevant disease models, treat diseases caused by genetics, assist in breeding in agricultural production, reduce biological stress, can be used for gene silencing or activation, and can also serve as a molecular diagnostic tool.
Figure 5: A dead Cas9 protein coupled with epigenetic modifiers which are used to repress certain genome sequences rather than cutting it all together. (Wikipedia)
ReferenceReference
[1] Sun, Q., van de Lisdonk, D., Ferrer, M. et al. Area postrema neurons mediate interleukin-6 function in cancer cachexia. Nat Commun 15, 4682 (2024). https://doi.org/10.1038/s41467-024-48971-1
[2] Fearon, K. C., Glass, D. J. & Guttridge, D. C. Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metab. 16, 153–166 (2012).
[3]Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. 2014 Sep 4;6(10):a016295. doi: 10.1101/cshperspect.a016295.
[4]https://en.wikipedia.org/wiki/Immunohistochemistry
[5]https://en.wikipedia.org/wiki/Fluorescence_in_situ_hybridization
[6]https://en.wikipedia.org/wiki/CRISPR_gene_editing