This review summarizes the recent findings from laboratory models of cancer cachexia that the release of extracellular vesicle-associated Hsp70 and Hsp90 by cancer activates Toll-like receptor 4 (TLR4) that provokes muscle catabolism by (1) direct activation of UPP and ALP in skeletal muscle cells through specific signaling pathways and (2) induction of systemic inflammation leading to the release of cytokines that also stimulate muscle protein degradation pathways. Here, HSP90AA1 is linked to cancer.