Molecular Mechanisms of Kaposi Sarcoma Development

Abstract

Kaposi’s sarcoma (KS) is a heterogeneous angioproliferative tumor that generally arises in the skin. At least four forms of this disease have been described, with the ‘HIV’-related form being the most aggressive and can involve mucosae or visceral organs. Three quarters of KS cases occur in sub-Saharan Africa (SSA) as geographic variation is explained by the disparate prevalence of KS-associated herpes virus (KSHV), which is the underlying cause of this disease. It can infect endothelial and/or mesenchymal cells that consequently transdifferentiate to an intermediate state. KSHV establishes a latent phase in host cells in which latency proteins and various non-coding RNAs (ncRNAs) play a complex role in proliferation and angiogenesis. It also undergoes periods of sporadic lytic reactivation triggered by various biological signals in which lytic stage proteins modulate host cell signaling pathways and are key in KS progression. Complex interactions with the microenvironment with production of inflammatory cytokines with paracrine signaling is a standout feature of KS development and maintenance. KSHV impairs the immune response by various mechanisms such as the degradation of a variety of proteins involved in immune response or binding to cellular chemokines. Treatment options include classical chemotherapy, but other novel therapies are being investigated.

The immune subtypes and landscape of sarcomas

“…In general, they lack significant mitotic activity, cytologic pleomorphism, and necrosis, while the spindle cells often stain positively with vascular marker, CD31, CD34, and FLI-1, as well as lymphatic endothelial markers, such as D2-40, by immunohistochemical staining [ 36 ]. Early lesions (plaque or patch) often appear as a granulation type reaction with immune cell infiltration, intense angiogenesis, and proliferating “spindle”-shaped cells of endothelial and macrophagic cell origin, which are the tumor cells of Kaposi sarcoma [ 37 ]. UPS, used as a synonym for malignant fibrous histiocytoma (MFH), may still represent a heterogeneous group of lesions with variable outcomes, but differing progenitor cells and complex karyotypes, modern genomic analysis and immunohistochemical staining techniques have allowed for the term to be more narrowly defined [ 38 ].…”

Imaging More than Skin-Deep: Radiologic and Dermatologic Presentations of Systemic Disorders

“…KS skin involvement is polymorphous, ranging from violaceous macules and papules ( Figure 21 A) to exophytic tumors with associated lymphedema. AIDS-related KS also frequently affects the upper body, head, and neck [ 88 , 89 , 90 , 91 , 92 , 93 ]. Twenty-two percent of patients manifest oral cavity lesions as the presenting sign.…”

Glucose and mannose analogs inhibit KSHV replication by blocking N‐glycosylation and inducing the unfolded protein response

“…This assumption is based on KSHV‐elicited inhibition of UPR downstream transcription factors, which are required to mitigate ER stress and restore ER homeostasis 12 . In summary, induction of ER stress by 2‐DG seems to be a promising strategy against KSHV 15 …”

“…12 In summary, induction of ER stress by 2-DG seems to be a promising strategy against KSHV. 15 A better understanding of the cellular mechanisms affected by 2-DG could offer new avenues for innovative therapies against KSHV. However, because 2-DG inhibits glycolysis and Nglycosylation, it is challenging to identify its molecular targets.…”

“…Besides being currently studied as an investigational drug against cancer, in recent years, 2‐DG has also been proposed as an antiviral agent acting through different mechanisms: by being pseudoincorporated into the structure of the viral capsid, by shutting off the building blocks required for viral replication through glycolysis inhibition, 13 , 14 and, as previously shown by our research group, by interfering with normal glycoprotein synthesis via ER stress and UPR activation. 8 , 15 Recently, a 2‐DG oral formulation was approved in India for emergency use as an adjunct therapy to treat moderate to severe coronavirus disease of 2019 (COVID‐19) patients. 16 Moreover, it has been shown that 2‐DG inhibits severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) multiplication in colon cancer cells.…”