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In addition, the SKM microenvironment includes factors such as lower extracellular matrix stiffness and altered lactic acid, pH, and oxygen levels, alongside anti-tumorigenic myokines and other secreted 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Kump   \nCitation: Kump, D.S. Mechanisms Underlying the Rarity of Skeletal Muscle Cancers. Int. J. Mol. Sci. 2024, 25, 6480. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms25126480  \nAcademic Editor: Andrea Telek  \nReceived: 7 May 2024  \nRevised: 4 June 2024  \nAccepted: 5 June 2024  \nPublished: 12 June 2024  \nCopyright: © 2024 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \nDepartment of Biological Sciences, Winston-Salem State University, 601 Martin Luther King Jr. Dr., Winston-Salem, NC 27110, USA; [kumpds@wssu.edu](kumpds@wssu.edu); Tel.: +1-336-750-8782  \nAbstract: Skeletal muscle (SKM), despite comprising ~40% of body mass, rarely manifests cancer. This review explores the mechanisms that help to explain this rarity, including unique SKM architecture and function, which prohibits the development of new cancer as well as negates potential metastasis to SKM. SKM also presents a unique immune environment that may magnify the anti-tumorigenic effect. Moreover, the SKM microenvironment manifests characteristics such as decreased extracellular matrix stiffness and altered lactic acid, pH, and oxygen levels that may interfere with tumor development. SKM also secretes anti-tumorigenic myokines and other molecules. Collectively, these mechanisms help account for the rarity of SKM cancer.  \nKeywords: cancer; epidemiology; immune; incidence; metastasis; microenvironment; myokine; prevention; skeletal muscle  \n1. Introduction  \nSkeletal muscle (SKM) comprises approximately 40–50% of body weight, depending on leanness [1–3]; nonetheless, primary SKM cancer is extremely rare [4–7], especially when organ mass is considered (Table 1) . When rare primary tumors occur in SKM, they most often derive from soft tissues during growth in childhood (particularly early childhood [age ≤10 years]) and include rhabdomyosarcoma and rhabdomyoma [8] . Rhabdomyosarcoma is recognized by light and electron microscopy as a tumor harboring cells that resemble myoblasts [9,10] . Despite the similarity with myoblasts, it is unclear whether rhabdomyosarcoma arises from myoblasts [11]; nonetheless, myoblasts likely undergo high proliferation during early childhood and adolescence to support SKM growth [12] and therefore could be the origin of the tumor. From 1975 to 1999, the incidence rate of rhabdomyosarcoma in the U.S. was 4.5/1 million for individuals aged \u003C20 years [13], which is similar to the rate of 4.9/1 million in Sweden in 2016 for individuals aged \u003C15 years [14]; the rate is lower in reported Asian populations [15], perhaps suggesting a genetic contribution. In the U.S., SKM cancers account for ~3.5% of pediatric cancers [16] .  \nIn adults, the incidence rate of rhabdomyosarcoma is estimated to be ~9.6/10 million. This rate was derived by multiplying the soft tissue cancer incidence rate of 3.2/100,000 [17] by 3%, which is the fraction of soft tissue sarcomas that rhabdomyosarcoma comprises [18]—the actual number is likely much lower, as the incidence rate is not age-specific, and thus inclusion of the pediatric population may skew the results higher; moreover, one website [19] lists the soft tissue sarcoma-to-rhabdomyosarcoma fraction in adults at 1%—if this is accurate, the incidence rate would be at least three times lower. Moreover, when the organ mass is considered (incidence rate per 100,000 per g of tissue), rhabdomyosarcoma manifests by far the lowest values among all cancers, at just 0.005%, 0.18%, 0.03%, 0.01%, and 0.0002% of the values for breast, brain, kidney, pancreas, and prostate cancers, respectively (Table 1) . Heart cancer has the","cbCaifcgQ4NMd4wU","https://ap.wps.com/l/cbCaifcgQ4NMd4wU","pdf",1695601,28,"English","# Introduction\n## Incidence and rarity of skeletal muscle cancers\n## Rhabdomyosarcoma and early-life origin\n## Adult incidence estimates and organ-mass comparison\n## Table 1 comparison of cancer incidence by organ and tissue mass","[{\"question\":\"Why are skeletal muscle cancers rare despite skeletal muscle mass being ~40% of the body?\",\"answer\":\"The review attributes rarity to SKM’s unique architecture and function that can prevent tumor development and limit metastasis, along with a distinctive immune environment and anti-tumorigenic microenvironment factors.\"},{\"question\":\"What tumor types and developmental timing does the review highlight when skeletal muscle cancers occur?\",\"answer\":\"When rare primary tumors arise in SKM, they most often derive from soft tissues during childhood, particularly early childhood (age ≤10 years), including rhabdomyosarcoma and rhabdomyoma.\"},{\"question\":\"Which microenvironment features may interfere with tumor development in skeletal muscle?\",\"answer\":\"The review describes decreased extracellular matrix stiffness and altered lactic acid, pH, and oxygen levels, which can interfere with tumor development, in addition to anti-tumorigenic myokines and other molecules.\"}]","Mechanisms Underlying the Rarity of Skeletal Muscle Cancers - Review | PDF",1789990629,71]