Editing Cachexia (section)

==Mechanism==
[[File:Cancer-associated cachexia diagram.jpg|thumb|Processes and mechanisms related to cancer-associated cachexia]]
The way cachexia works is not well understood, but research suggests it is linked to  inflammation, changes in metabolism, and hormone changes in the body .<ref name="ferrer-2023" />

=== Inflammatory ===
Certain molecules in the body, called [[Inflammatory cytokine]]s, play a big role in causing cachexia. Two important ones are [[tumor necrosis factor|tumor necrosis factor (TNF)]] and [[interleukin 6|interleukin 6 (IL-6)]].<ref name="fearon-2012" />

==== Tumor Necrosis Factor (TNF) ====
TNF breaks down muscle and fat while stopping new muscle and fat cells from forming by activating the [[ubiquitin proteasome pathway]].<ref name="ferrer-2023" /><ref name="fearon-2012" /><ref name="Kumar" /><ref name="petruzzelli-2016">{{Cite journal |last1=Petruzzelli |first1=Michele |last2=Wagner |first2=Erwin F. |date=2016-03-01 |title=Mechanisms of metabolic dysfunction in cancer-associated cachexia |journal=Genes & Development |language=en |volume=30 |issue=5 |pages=489–501 |doi=10.1101/gad.276733.115 |issn=0890-9369 |pmc=4782044 |pmid=26944676}}</ref><ref name="nishikawa-2021" /><ref name="setiawan-2023">{{Cite journal |last1=Setiawan |first1=Tania |last2=Sari |first2=Ita Novita |last3=Wijaya |first3=Yoseph Toni |last4=Julianto |first4=Nadya Marcelina |last5=Muhammad |first5=Jabir Aliyu |last6=Lee |first6=Hyeok |last7=Chae |first7=Ji Heon |last8=Kwon |first8=Hyog Young |date=2023-05-22 |title=Cancer cachexia: molecular mechanisms and treatment strategies |journal=Journal of Hematology & Oncology |language=en |volume=16 |issue=1 |page=54 |doi=10.1186/s13045-023-01454-0 |doi-access=free |issn=1756-8722 |pmc=10204324 |pmid=37217930}}</ref> It also triggers the release of other cytokines that also speed up muscle loss. Since this process is very complex, cachexia is unlikely to be caused by one molecule.<ref name="petruzzelli-2016" /> While it is thought to be produced by immune cells called [[macrophage]]s, scientists are still unsure of exactly where TNF is produced in cachexia.<ref name="fearon-2012" />

==== Interleukin-6 (IL-6) ====
IL-6 is thought to cause muscle loss by starting a pathway called the [[JAK-STAT signaling pathway|JAK/STAT pathway]].<ref name="ferrer-2023" /><ref name="fearon-2012" /><ref name="setiawan-2023" /><ref>{{Cite journal |last1=Moresi |first1=Viviana |last2=Adamo |first2=Sergio |last3=Berghella |first3=Libera |date=2019-04-30 |title=The JAK/STAT Pathway in Skeletal Muscle Pathophysiology |journal=Frontiers in Physiology |volume=10 |page=500 |doi=10.3389/fphys.2019.00500 |doi-access=free |issn=1664-042X |pmc=6502894 |pmid=31114509}}</ref> IL-6 is produced by immune cells called macrophages, potentially producing [[acute phase reactants]] which may worsen muscle loss.<ref name="fearon-2012" /><ref name="petruzzelli-2016" />

Other molecules may include:

* [[Myostatin]] - Prevents muscle growth and is often higher in people with cancer.<ref name="fearon-2012" /><ref name="petruzzelli-2016" /><ref name="argiles-2016">{{cite journal |vauthors=Argilés JM, Campos N, Lopez-Pedrosa JM, Rueda R, Rodriguez-Mañas L |date=September 2016 |title=Skeletal Muscle Regulates Metabolism via Interorgan Crosstalk: Roles in Health and Disease |journal=Journal of the American Medical Directors Association |volume=17 |issue=9 |pages=789–96 |doi=10.1016/j.jamda.2016.04.019 |pmid=27324808 |doi-access=free}}</ref>
* Activin - May contribute to muscle loss when TNF is also active.<ref name="fearon-2012" /><ref name="petruzzelli-2016" />
* Growth Differentiation Factor 15 (GDF-15) - Normally produced during cellular stress. Thought to play a role in food aversion and is associated with reduced food intake.<ref name="ferrer-2023" />

=== Metabolic ===
Cachexia can also result from changes in metabolism. Tumors sometimes release molecules that break down fat and muscle, causing cachexia by making it harder for the body to keep up with energy needs.<ref name="nishikawa-2021" /> These molecules include lipid mobilizing factor, [[proteolysis-inducing factor]], and [[Uncoupling protein|mitochondrial uncoupling proteins]].<ref name="nishikawa-2021" /><ref>{{cite journal | vauthors = Martignoni ME, Kunze P, Friess H | title = Cancer cachexia | journal = Molecular Cancer | volume = 2 | issue = 1 | pages = 36 | date = November 2003 | pmid = 14613583 | pmc = 280692 | doi = 10.1186/1476-4598-2-36 | doi-access = free }}</ref> In addition, uncontrolled inflammation in people with cachexia increases the body's need for nutrients.<ref name="setiawan-2023" /><ref name="argiles-2016" />

The way the body uses nutrients is also changed in cachexia. People with cachexia can have loss of appetite, are less responsive to insulin, and can have increased fat breakdown, all of which make it difficult for the body to properly use food. This is especially true in people with cancer.<ref name="petruzzelli-2016" />

=== Hormonal ===
[[Hormone]]s are signaling molecules used to regulate bodily behavior and are believed to play a role in cachexia as well.

[[Glucocorticoid]]s are produced as part of the body's natural response to stress. They are also known to play a role in muscle breakdown.<ref name="fearon-2012" /><ref>{{Cite journal |last1=Salehian |first1=Behrouz |last2=Kejriwal |first2=Kamal |date=1999 |title=Glucocorticoid-Induced Muscle Atrophy: Mechanisms And Therapeutic Strategies |url=https://linkinghub.elsevier.com/retrieve/pii/S1530891X20402952 |journal=Endocrine Practice |language=en |volume=5 |issue=5 |pages=277–281 |doi=10.4158/EP.5.5.277|pmid=15251668 |url-access=subscription }}</ref> Furthermore, people with long-term illness such as cancer are frequently treated with glucocorticoids, making cachexia more likely in these individuals.<ref name="fearon-2012" />

Some tumors produce a molecule called parathyroid-related peptide (PTHrP). It increases metabolism by stimulating energy production in the [[Mitochondrion|mitochondria]] of fat cells.<ref name="petruzzelli-2016" /><ref name="nishikawa-2021" /><ref name="setiawan-2023" />

[[Leptin]] is a hormone known to decrease appetite. People with cachexia often have high leptin levels, making them feel less hungry.<ref name="nishikawa-2021" />

The [[hypothalamus]], the brain's appetite control center, is also affected in cachexia. Given the hypothalamic function in controlling appetite, it is believed to play a role in cachexia.<ref name="ferrer-2023" /> The appetite-controlling center of the hypothalamus is controlled by neuropeptide Y (NPY) and agouti gene-related protein (AgRP) that increase appetite, as well as proopiomelanocortin (POMC) and cocaine and amphetamine-regulated transcrip (CART) that decrease appetite.<ref name="nishikawa-2021" /><ref name="setiawan-2023" /> Inflammation may disrupt these appetite signals, causing reduced hunger and leading to further weight and muscle loss. However, scientists are still studying exactly how this process works.<ref name="petruzzelli-2016" /><ref name="nishikawa-2021" /><ref name="setiawan-2023" />