Materiały źródłowe

• #1 Kaposi Sarcoma Pathogenesis: A Triad of Viral Infection, Oncogenesis and Chronic Inflammation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3472629/

  Kaposi sarcoma (KS) is a complex cancer that arises from the initial infection of an appropriate endothelial or progenitor cell by Kaposi Sarcoma Herpesvirus/Human Herpesvirus-8 (KSHV/HHV8). […] Cellular hallmarks of KS progression include both the hyper-proliferation of KSHV-infected cells and the infiltration of immune modulatory cells into KS lesions, which together result in chronic inflammation, the induction of angiogenesis and tumor growth. […] The co-factors involved in classic and endemic KS have yet to be definitively elucidated. Various environmental and genetic factors have been implicated, as well as age, sex and malnutrition. […] The association of KS with the Koebner phenomenon, a condition where lesions initiate or recur at inflammatory sites of injury or trauma and the recrudescent KS (KS flare) seen with the immune constitution inflammatory syndrome (IRIS) suggest that inflammation plays a contributing role in oncogenesis.

• #1 Kaposi Sarcoma, a Trifecta of Pathogenic Mechanisms

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9140574/

  Kaposis sarcoma is a rare disease with four known variants: classic, epidemic, endemic and iatrogenic (transplant-related), all caused by an oncogenic virus named Human Herpes Virus 8. […] The viral infection in itself, along with the oncogenic properties of HHV8 and with immune system dysfunction, forms the grounds on which Kaposis Sarcoma may develop. […] Chronic inflammation and oncogenesis are promoted by a mix of viral genes that directly promote cell survival and transformation or interfere with the regular cell cycle and cell signaling (of particular note: LANA-1, v-IL6, vBCL-2, vIAP, vIRF3, vGPCR, gB, K1, K8.1, K15). […] All four variants described involve Kaposis sarcoma-associated herpesvirus (KSHV), but by itself the virus is not enough to start the oncogenic process. […] Currently KS is defined as a human herpes virus 8 (HHV8) associated angioproliferative disease. Kaposis sarcoma is a trifecta of pathogenic mechanisms and develops only when a mix of viral infection, oncogenesis and chronic inflammation occur.

• #1 Kaposi Sarcoma, a Trifecta of Pathogenic Mechanisms

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9140574/

  A combination of a compromised immune system (whether achieved through medication or through a condition such as AIDS), genetic predisposition and environmental factors is needed for oncogenesis. […] The lesion, at the start at least, is considered reactive in nature (a reactive angioproliferative response towards HHV8), and only after the continued effects of the viral genes along with disruption of cell cycle arrest points, cytokine stimulation and local inflammation, can the KSHV-infected endothelial cells become a true neoplasm. […] LANA-1, the major protein expressed during the latent phase, upregulates vFlip (which has antiapoptotic functions) and vCyclin (overcomes cell cycle arrest of RB through phosphorylation) and stabilizes beta-catenin (through interaction with GSK-3beta) and c-Myc (LANA decreases c-Myc phosphorylation thus inhibiting c-Myc induced apoptosis) and also inhibits the p53 tumor suppressor gene.

• #1 Kaposi Sarcoma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/279734-overview

  Immune activation may also be a factor in Kaposi sarcoma, with a role for inflammatory cytokines such as gamma interferon and the initiation of HHV-8 infected cell proliferation by HIV-tat protein. […] This complex interaction of HIV, HHV-8, environmental factors, and the immune system requires further investigation to attempt to decipher the true pathogenesis of Kaposi sarcoma. […] Kaposi sarcoma is caused by an excessive proliferation of spindle cells that are thought to have an endothelial cell origin. […] KSHV contains a large genome with greater than 85 antigenically competent genes. […] Human herpes virus 8 (HHV-8) genomic sequences have been identified by polymerase chain reaction in more than 90% of all types of Kaposi sarcoma lesions (including epidemic and endemic forms), suggesting a causative role for this DNA virus.

• #1 Kaposi’s sarcoma pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Kaposi%27s_sarcoma_pathophysiology

  Kaposi’s sarcoma arises from endothelial cells, which are epithelial cells that normally lines the luminal surface of blood vessels and lymphatic vessels. […] Kaposi’s sarcoma is mainly caused by an infection with Human herpes virus 8 (HHV-8), which is also known as Kaposi’s sarcoma-associated herpes virus (KSHV). […] A state of immunosuppression facilitates the development of Kaposi’s sarcoma among patients infected with the virus. […] Kaposi’s sarcoma is characterized by abnormal proliferation of endothelial cells, neoangiogenesis, and inflammation. […] The oncogenesis of HHV-8 infection is due to a number of human cellular genes that have been incorporated through molecular piracy into the viral DNA sequence. […] The augmentation of such cellular proliferation pathways will protect the virus from the immune system and allow a continuous viral replication during the latency period.

• #1 Kaposi Sarcoma Pathogenesis: A Triad of Viral Infection, Oncogenesis and Chronic Inflammation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3472629/

  Like all herpesviruses, KSHV establishes a life-long infection in the host that depends upon virus-encoded immune evasion genes and genes that influence cellular proliferation, survival, migration, angiogenesis and cytokine/chemokine production. […] Understanding the dynamic relationship between host and viral factors that drives KS oncogenesis is central to mounting effective strategies to prevent or ameliorate tumor development. […] The role of the KSHV lytic cycle in KS tumorigenesis is also a matter of debate. […] While KSHV latent genes are essential for genome maintenance, lytic genes probably play an important role in driving tumorigenesis via direct as well as paracrine mechanisms. […] Most of the pro-inflammatory cytokines and angiogenic factors produced or induced by KSHV have likely evolved to create a highly proliferative environment that favors viral genome maintenance as well as the consistent, yet low level of reactivation from latency.

• #1 Molecular Mechanisms of Kaposi Sarcoma Development

  https://www.mdpi.com/2072-6694/14/8/1869

  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. 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. 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. […] KSHV, also known HHV8, is a double-stranded linear DNA gamma-herpesvirus and is the causal agent of all forms of Kaposi sarcomas. It can infect a variety of cell types using viral envelope glycoproteins, including monocytes, dendritic cells, fibroblasts, B cells, and endothelial cells. KSHV establishes latency in host cells (endothelial cells, mesenchymal cells, and B cells in this case), responsible for lifelong infection. During latency, only a few genes from the latency locus are expressed, such as open reading frame (ORF)71 (v-FLIP), ORF72 (v-Cyclin), ORF73 (latency-associated nuclear antigen, or LANA), and the K12 region (which gives rise to at least 12 viral miRNAs). Latent gene-encoded proteins ensure cell survival by several different mechanisms like the inhibition of apoptosis or by stimulation of the nuclear factor-κB (NF-κB) pathway.

• #1 Pathogenesis of Kaposi’s sarcoma.

  https://vivo.weill.cornell.edu/display/pubid12852653

  Kaposi’s sarcoma (KS) is a disease characterized by proliferative vascular lesions, which almost invariably contain the KS-associated herpesvirus (KSHV), also called human herpesvirus 8. KSHV is a lymphotrophic and angiotrophic herpesvirus, whose genome encodes several proteins involved in proliferation, antiapoptotic functions, and inflammation. Most KS spindle cells express latent KSHV genes, but a few express lytic genes, which might be involved in angiogenic and paracrine mechanisms that contribute to KS pathogenesis. […] A number of tissue culture and mouse models have been established, but a comprehensive system that accurately portrays KS pathogenesis still does not exist.

• #1 Molecular Mechanisms of Kaposi Sarcoma Development

  https://www.mdpi.com/2072-6694/14/8/1869

  The activation of lytic cycles is also associated with the production of viral proteins that play a key role in KS tumor progression and are detectable in KS lesions. These include viral oncogenes and intracellular or membrane proteins, such as vGPCR, which is an analog of IL-8R (not requiring the presence of the ligand to deliver the signal). vGPCR induces the production of cytokines such as PDGF and VEGF, which is considered important for the development of the lesions. […] The infection of endothelial cells with KSHV results in cell transformation, accompanied by complex interactions with the microenvironment. Infected cells produce cytokines that induce paracrine signaling, including vascular endothelial growth (VEGF), PDGF, FGF, and interleukin 6 (IL-6). These cytokines are implicated in the development and maintenance of KS.

• #1 Kaposi Sarcoma, a Trifecta of Pathogenic Mechanisms

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9140574/

  v-IL6, a protein expressed both during the latent (at lower but functional levels) and lytic viral phase of KSHV, plays an important role in KS genesis through angiogenesis, cell proliferation and invasion via downregulation of caveolin 1 (CAV1). […] vBCL-2 serves as both a way to extend cell survival via apoptosis inhibition and also evade the autophagic innate system. […] K1 plays an important role in lytic replication, cellular survival and immortalization of human endothelial cells. […] Kaposis sarcoma development is somewhat different (but not unique). It can promote VEGF-A secretion in normoxic conditions by several methods by way of KSHV proteins. […] KSHV genes that contribute to the stabilization of HIF-1 include LANA-1, vIRF3 and viral G-protein coupled receptor (vGPCR). […] Direct secretion of VEGF-A is promoted by viral products such as glycoprotein b (gB), K1, K8.1, vIL-6 and miRNAs (via downregulation of THBS1).

• #1 Kaposi Sarcoma, a Trifecta of Pathogenic Mechanisms

  https://www.mdpi.com/2075-4418/12/5/1242

  KSHV additionally encodes three chemokine homologs known as viral CC-chemokine ligand 1 (vCCL1; encoded by K6), vCCL2 (K4) and vCCL3 (K4.1). […] The viral infection in itself, along with the oncogenic properties of HHV8 and with immune system dysfunction, forms the grounds on which Kaposi’s Sarcoma may develop.

• #1 Kaposi Sarcoma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/279734-overview

  The current working hypothesis is that HHV-8 must be present for the disease to develop. […] Factors that are thought to contribute to the development of Kaposi sarcoma in individuals infected with HHV-8 and HIV include an abnormal cytokine milieu associated with HIV infection, and involving the following angiogenic cytokines: Interleukin-1 (IL-1) beta, Basic fibroblast growth factor (bFGF), Acidic fibroblast growth factor, Endothelial growth factor, Vascular endothelial growth factor (VEGF). […] Oncostatin M, IL-1, IL-6, fibroblast growth factor, tumor necrosis factor (TNF), and the HIV-tat protein all of which originate from HIV-infected T cells act as costimulants for Kaposi sarcoma cells. […] A specific viral gene, ORF74, encodes for a G-protein coupled receptor that causes production of VEGF and other angiogenic mediators.

• #1 Kaposi Sarcoma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/279734-overview

  Thus, Kaposi sarcoma may be caused by HHV-8 (KSHV) with stimulation by autocrine and paracrine growth factors secreted by the spindle cells themselves as well as the supporting network of mononuclear and endothelial cells. Coinfection with HIV may create a more aggressive course, which is mitigated by effective antiretroviral therapies. […] In summary, complex immune dysregulation is the center theme for the pathogenesis of Kaposi sarcoma. This includes cellular immunity defects, humoral immunity defects and abnormalities of vascular endothelial growth factor. Apparent overlapping mechanisms for upregulation of multiple pathways produce the malignant phenotype.

• #1 Kaposi Sarcoma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/279734-overview

  Kaposi sarcoma (KS) is an indolent angio-proliferative spindle-cell tumor derived from endothelial and immune cells infected with human herpes virus type 8 (HHV-8; also known as Kaposi sarcoma herpes virus [KSHV]). HHV-8 is identified as the causative agent of KS; it is present in 95-98% of all cases. […] Although all types of KS have in common infection with HHV-8, each has a distinct clinical course. Therefore, it is likely that other factors, such as extent and type of immune suppression, influence the disease. […] The common theme of immune dysregulation is associated with all 4 types of Kaposi sarcoma. Diminished responsiveness of cytotoxic T-lymphocytes is associated with Kaposi sarcoma pathogenesis. […] Restoration of natural killer cell cytoxic effect may explain regression of Kaposi sarcoma in AIDS patients treated with antiretrovirla therapy.

• #1

  https://www.jci.org/articles/view/40567

  However, these facts also imply something equally important: that while necessary for KS development, KSHV infection is not sufficient for it. […] The exact mechanisms by which HIV amplifies KS risk during KSHV infection remain contentious. […] Laboratory experiments indicate that in certain settings, HIV infection can augment KSHV replication, in both cell-autonomous and paracrine fashions. […] The bimodal expression program of the KSHV genome requires that, when considering the pathogenetic roles of viral genes, careful attention be paid to which program of viral gene expression governs transcription of that gene; failure to do so can invite misinterpretation. […] The best characterized latent genes constitute a major latency locus that is transcribed in all latently infected cells.

• #1 Pathogenesis of AIDS-Related Kaposi’s Sarcoma

  https://www.cancernetwork.com/view/pathogenesis-aids-related-kaposis-sarcoma

  Although the late Dr. Thomas was actually referring to bacterial sepsis, his statement could easily have applied to the cytokine „storm” of HIV infection and Kaposi’s sarcoma (KS). This cytokine dysregulation, nicely described in the article by the UCLA group, is one of the major culprits responsible for the proliferation of KS in HIV-infected patients. The abnormally high cytokine levels are produced not only by HIV infection and opportunistic and nonopportunistic infections but also by the KS cells themselves. […] The tremendous synergy between cytokines and the HIV tat protein provides a possible insight into why AIDS-related KS (AIDS/KS) is much more virulent than the classic Mediterranean form of KS in older men, in which HIV tat protein would not be expected to play any role. […] The laboratory correlate of these clinical observations is the in vitro stimulation of AIDS/KS cells by dexamethasone. Furthermore, simultaneous exposure to dexamethasone and oncostatin-M (Onco-M), a major cytokine involved in the pathogenesis of KS, produces a dramatic synergistic effect on the proliferation of AIDS/KS cells, suggesting an interaction between glucocorticoid and growth factor intracellular pathways in these cells.

• #1 Cancer prevention and control: Kaposi’s sarcoma – ecancer

  https://ecancer.org/es/journal/article/951-cancer-prevention-and-control-kaposis-sarcoma

  Kaposis sarcoma (KS) is a vascular tumour of endothelial origin that is associated with human herpes virus-8 infection. […] For decades, the aetiology and pathogenesis of KS was unknown. In 1994, Chang et al. reported the discovery of the KSHV, also known as human herpes virus-8 (HHV-8), and demonstrated an etiological link between the virus and KS. KSHV induces angiogenic and inflammatory cytokines, as well as gene products implicated in angiogenesis; HIV infection further potentiates the development of KS through the transactivation (Tat) protein, which acts as a growth factor for KS. The Tat protein induces endothelial cell proliferation and facilitates the invasion of extracellular matrix. […] From the clinical perspective, since the majority of tumour cells are latently infected with KSHV, lytic replication plays a major role in disease progression and virus dissemination. Therefore, transformation to lytic cycle could be a preventive strategy by increasing targets through augmented cell replication.

• #1

  https://link.springer.com/article/10.1007/s13555-016-0152-3

  The lesions found in KS are known to contain several cell types, such as infiltrating inflammatory cells, endothelium and spindle cells, which have been postulated to derive from either vascular or lymphatic precursors. […] In HIV-infected individuals, Th1-type cytokines have been suggested to potentiate KSHV activation, which can lead to an increased viral load and a greater likelihood of the development of KS. […] Also, HIV-1-associated trans-activating regulatory (Tat) protein is needed for replication of the HIV virus and is also released from acutely infected T cells. This protein may induce KS by stimulating proangiogenic chemokines, and by enhancing KS cell growth by synergizing with basic fibroblast growth factor (bFGF), which is an essential factor for lesion formation. […] However, the Tat protein is only able to interact with endothelial cells through a RGD motif, which is absent in HIV-2. This may explain why KS is less commonly found in individuals with HIV-2 compared to HIV-1 infection.

• #1 Pathogenesis of AIDS-Related Kaposi’s Sarcoma

  https://www.cancernetwork.com/view/pathogenesis-aids-related-kaposis-sarcoma

  High levels of IL-6 have been found in patients with KS and may precede the development of the disease in HIV-infected men. […] This striking association has quelled much of the previous controversy regarding the roles of cytomegalovirus, Epstein-Barr virus, human papilloma virus, mycoplasma, and inhaled nitrites in the pathogenesis of KS. […] The authors’ model of the pathogenesis of KS is plausible. In brief, they suggest the following steps in pathogenesis: transformation of normal mesenchymal cells to a „pre-KS” cell by KSHV; proliferation and differentiation of the KS tumor stimulated by the cytokine dysregulation brought on by HIV infection, opportunistic and nonopportunistic infections, and the KS cells themselves; further proliferation of the KS tumor induced by the synergy between cytokines and the HIV tat protein and, in certain clinical settings, by the synergy between cytokines and exogenous steroids; and transformation of KS into a more malignant phenotype as HIV induces greater immunosuppression and as tumors enlarge.

• #1 A Novel Mechanism Inducing Genome Instability in Kaposi’s Sarcoma-Associated Herpesvirus Infected Cells | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1004098

  Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic herpesvirus associated with multiple AIDS-related malignancies. […] Evidence suggests that KSHV lytic replication can cause genome instability in KSHV-infected cells, although no mechanism has thus far been described. […] Herein, we show that lytically active KSHV infected cells induce a DNA damage response and, importantly, we demonstrate directly that this is due to DNA strand breaks. […] Moreover, we describe a novel mechanism showing that the genetic instability observed is a consequence of R-loop formation. […] Our data provide a model of R-loop induced DNA damage in KSHV infected cells and describes a novel system for studying genome instability caused by aberrant hTREX. […] Specifically, lytic infection of cells has been shown to directly induce DNA double-strand breaks, a severe form of genome instability.

• #1 A Novel Mechanism Inducing Genome Instability in Kaposi’s Sarcoma-Associated Herpesvirus Infected Cells | PLOS Pathogens

  https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1004098

  Importantly however, there is currently no known mechanism that describes how KSHV lytic replication can cause DNA double-strand breaks. […] We therefore set out to investigate whether the known interaction between ORF57 and hTREX could have implications for genome instability in KSHV lytically infected cells. […] Herein, we demonstrate that sequestration of hTREX by the KSHV ORF57 protein is sufficient to induce genome instability, due to a consequence of the formation of R-loops. […] Together, these observations highlight the importance of the hTREX complex, not only in exporting mRNAs from the nucleus, but also in maintaining genome integrity during transcription. […] Our model proposes that aberrant hTREX levels, sequestered by ORF57, leads to the formation of R-loops, which in turn increases the number of DNA DSBs and the rate of mutation. […] This model explains for the first time a possible novel mechanism of lytic KSHV induced DNA double-strand breaks. […] Our work highlights a novel mechanism by which KSHV can induce genome instability in infected cells, an enabling characteristic of the hallmarks of cancer.

• #1

  https://www.jci.org/articles/view/40567

  The linkage of Kaposi sarcoma (KS) to infection by a novel human herpesvirus (Kaposi sarcoma-associated herpesvirus [KSHV]) is one of the great successes of contemporary biomedical research and was achieved by using advanced genomic technologies in a manner informed by a nuanced understanding of epidemiology and clinical investigation. […] Ongoing efforts to understand the molecular mechanisms by which KSHV infection predisposes to KS continue to be powerfully influenced by insights emanating from the clinic. […] This review discusses the proposed mechanisms underlying the association of KSHV with KS, with particular emphasis on how they relate to the distinctive clinical and pathologic features of this unique human neoplasm. […] From a pathogenetic viewpoint, it is helpful to think of KS as being composed of three parallel processes: proliferation (principally affecting spindle cells), inflammation, and angiogenesis.

• #1

  https://www.jci.org/articles/view/40567

  Unlike traditional cancer, which is predominantly a proliferative state driven by tumor cells that have achieved substantial autonomy and only later trigger inflammatory and angiogenic responses, KS is a disease in which all three processes participate simultaneously from its inception and are continuously necessary for the lesion to progress. […] A useful synthesis envisions that spindle cells produce proinflammatory and proangiogenic factors that recruit inflammatory cells and neovascular elements; these in turn provide growth factors and other substances necessary for spindle cell survival and proliferation. […] The discovery of the KSHV genome allowed rapid development of both PCR tests for viral DNA and serologic tests for antiviral antibodies. […] Taken together, these facts strongly imply that KSHV is the agent predicted by KS epidemiology and is necessary for KS development KS is never observed in the absence of KSHV.

• #1 Kaposi’s Sarcoma-associated Herpesvirus vFLIP Promotes MEndT to Generate Hybrid M/E State for Tumorigenesis | bioRxiv

  https://www.biorxiv.org/content/10.1101/2021.05.04.442576.full

  Kaposi’s sarcoma (KS) is an angioproliferative and invasive tumor caused by Kaposi’s sarcoma-associated herpesvirus (KSHV). The cellular origin of KS tumor cells remains contentious. Recently, evidence has accrued indicating that KS may arise from KSHV-infected mesenchymal stem cells (MSCs) through mesenchymal-to-endothelial transition (MEndT), but the transformation process has been largely unknown. […] In this study, we investigated the KSHV-mediated MEndT process and found that KSHV infection rendered MSCs incomplete endothelial lineage differentiation and formed hybrid mesenchymal/endothelial (M/E) state cells characterized by simultaneous expression of mesenchymal markers PDGFRA/Nestin and endothelial markers PDPN/CD31. The hybrid M/E cells have acquired high tumorigenic properties in vitro and the potential to form KS-like tumors after transplanted in mice under renal capsules.

• #1 Kaposi’s Sarcoma-associated Herpesvirus vFLIP Promotes MEndT to Generate Hybrid M/E State for Tumorigenesis | bioRxiv

  https://www.biorxiv.org/content/10.1101/2021.05.04.442576.full

  Furthermore, the genetic analysis identified KSHV-encoded FLICE inhibitory protein (vFLIP) as a crucial regulator controlling KSHV-induced MEndT and generating hybrid M/E state cells for tumorigenesis. Overall, KSHV-mediated MEndT that transforms MSCs to tumorigenic hybrid M/E state cells driven by vFLIP is an essential event in Kaposi’s sarcomagenesis. […] Increasing evidence supports that KS derives from KSHV-infected MSC through MEndT. However how KSHV infection drives mesenchymal stem cell for MEndT process that leads to Kaposi’s sarcoma was largely unknown. […] We found that KSHV infection initiates an endothelial lineage, but incomplete differentiation that generates tumor cells with hybrid mesenchymal and endothelial phenotypes. Such hybrid M/E cells exhibit oncogenic properties and form KS-like lesions in Kidney capsule transplantation.

• #1 Pathogenesis of AIDS-Related Kaposi’s Sarcoma

  https://www.cancernetwork.com/view/pathogenesis-aids-related-kaposis-sarcoma

  New treatments based on the pathogenesis of KS, as the authors note, are a direct consequence of this model; these treatments involve inhibition of KSHV, inhibition of cytokine production or blockade of cytokine receptors, inhibition of angiogenesis, and blockade of intracellular signal transduction.

• #2 Kaposi’s sarcoma – Wikipedia

  https://en.wikipedia.org/wiki/Kaposi%27s_sarcoma

  Kaposi’s sarcoma (KS) is caused by a combination of immune suppression (such as due to HIV/AIDS) and infection by Human herpesvirus 8 (HHV8 also called KS-associated herpesvirus (KSHV)). […] KSHV encodes oncogenes, microRNAs and circular RNAs that promote cancer cell proliferation and escape from the immune system. […] KS may arise as a cancer of lymphatic endothelium and forms vascular channels that fill with blood cells, giving the tumor its characteristic bruise-like appearance. […] The spindle cells of Kaposi sarcoma differentiate toward endothelial cells, probably of lymph vessel rather than blood vessel origin.

• #2 Kaposi Sarcoma, a Trifecta of Pathogenic Mechanisms

  https://www.mdpi.com/2075-4418/12/5/1242

  Kaposi’s sarcoma is a rare disease with four known variants: classic, epidemic, endemic and iatrogenic (transplant-related), all caused by an oncogenic virus named Human Herpes Virus 8. The viral infection in itself, along with the oncogenic properties of HHV8 and with immune system dysfunction, forms the grounds on which Kaposi’s Sarcoma may develop. […] All four variants described involve Kaposi’s sarcoma-associated herpesvirus (KSHV), but by itself the virus is not enough to start the oncogenic process. The second common factor is immunosuppression, or a malfunctioning immune system. Currently KS is defined as a human herpes virus 8 (HHV8) associated angioproliferative disease. Kaposi’s sarcoma is a trifecta of pathogenic mechanisms and develops only when a mix of viral infection, oncogenesis and chronic inflammation occur.

• #2 Kaposi Sarcoma, a Trifecta of Pathogenic Mechanisms

  https://www.mdpi.com/2075-4418/12/5/1242

  A combination of a compromised immune system (whether achieved through medication or through a condition such as AIDS), genetic predisposition and environmental factors is needed for oncogenesis. […] The lesion, at the start at least, is considered reactive in nature (a reactive angioproliferative response towards HHV8), and only after the continued effects of the viral genes along with disruption of cell cycle arrest points, cytokine stimulation and local inflammation, can the KSHV-infected endothelial cells become a true neoplasm. […] LANA-1, the major protein expressed during the latent phase, upregulates vFlip (which has antiapoptotic functions) and vCyclin (overcomes cell cycle arrest of RB through phosphorylation) and stabilizes beta-catenin (through interaction with GSK-3beta) and c-Myc (LANA decreases c-Myc phosphorylation thus inhibiting c-Myc induced apoptosis) and also inhibits the p53 tumor suppressor gene.

• #2 Kaposi Sarcoma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/279734-overview

  The current working hypothesis is that HHV-8 must be present for the disease to develop. […] Factors that are thought to contribute to the development of Kaposi sarcoma in individuals infected with HHV-8 and HIV include an abnormal cytokine milieu associated with HIV infection, and involving the following angiogenic cytokines: Interleukin-1 (IL-1) beta, Basic fibroblast growth factor (bFGF), Acidic fibroblast growth factor, Endothelial growth factor, Vascular endothelial growth factor (VEGF). […] Oncostatin M, IL-1, IL-6, fibroblast growth factor, tumor necrosis factor (TNF), and the HIV-tat protein all of which originate from HIV-infected T cells act as costimulants for Kaposi sarcoma cells. […] A specific viral gene, ORF74, encodes for a G-protein coupled receptor that causes production of VEGF and other angiogenic mediators.

• #2

  https://www.jci.org/articles/view/40567

  However, these facts also imply something equally important: that while necessary for KS development, KSHV infection is not sufficient for it. […] The exact mechanisms by which HIV amplifies KS risk during KSHV infection remain contentious. […] Laboratory experiments indicate that in certain settings, HIV infection can augment KSHV replication, in both cell-autonomous and paracrine fashions. […] The bimodal expression program of the KSHV genome requires that, when considering the pathogenetic roles of viral genes, careful attention be paid to which program of viral gene expression governs transcription of that gene; failure to do so can invite misinterpretation. […] The best characterized latent genes constitute a major latency locus that is transcribed in all latently infected cells.

• #2 Molecular Mechanisms of Kaposi Sarcoma Development

  https://www.mdpi.com/2072-6694/14/8/1869

  Oncogenic DNA viruses produce oncogenic proteins responsible for cellular proliferation and the protection of the host cell against apoptosis. They evade the host immune surveillance system by multiple mechanisms such as the reduction of viral gene expression to limit the amount of viral antigen presentation, the synthesis of critical proteins affecting the process of antigen presentation, and the expression of various viral “immunoevasins” that manipulate host cells to reduce immunogenicity. Following KSHV infection of endothelial cells (or mesenchymal stem cells), it establishes a latent phase, expressing a limited set of genes, including LANA (ORF73), vFLIP (ORF71), vCyclin (ORF72), Kaposins (ORFK12), and a set of miRNAs. Some of these proteins are analogs of cellular genes (FLIP, Cyclin D) and have oncogenic properties in vitro in cell cultures.

• #2 Kaposi Sarcoma, a Trifecta of Pathogenic Mechanisms

  https://www.mdpi.com/2075-4418/12/5/1242

  v-IL6, a protein expressed both during the latent (at lower but functional levels) and lytic viral phase of KSHV, plays an important role in KS genesis through angiogenesis, cell proliferation and invasion via downregulation of caveolin 1 (CAV1). […] vBCL-2 serves as both a way to extend cell survival via apoptosis inhibition and also evade the autophagic innate system. […] vCyclin accelerates cell-cycle progression and also promotes apoptosis in cells with increased levels of CDK6. […] K1 plays an important role in lytic replication, cellular survival and immortalization of human endothelial cells. […] Kaposi’s sarcoma development is somewhat different (but not unique). It can promote VEGF-A secretion in normoxic conditions by several methods by way of KSHV proteins. […] KSHV infected cells also demonstrate an increased endothelial permeability due to the downregulation and degradation of VE-cadherin.

• #2 Kaposi Sarcoma, a Trifecta of Pathogenic Mechanisms

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9140574/

  v-IL6, a protein expressed both during the latent (at lower but functional levels) and lytic viral phase of KSHV, plays an important role in KS genesis through angiogenesis, cell proliferation and invasion via downregulation of caveolin 1 (CAV1). […] vBCL-2 serves as both a way to extend cell survival via apoptosis inhibition and also evade the autophagic innate system. […] K1 plays an important role in lytic replication, cellular survival and immortalization of human endothelial cells. […] Kaposis sarcoma development is somewhat different (but not unique). It can promote VEGF-A secretion in normoxic conditions by several methods by way of KSHV proteins. […] KSHV genes that contribute to the stabilization of HIF-1 include LANA-1, vIRF3 and viral G-protein coupled receptor (vGPCR). […] Direct secretion of VEGF-A is promoted by viral products such as glycoprotein b (gB), K1, K8.1, vIL-6 and miRNAs (via downregulation of THBS1).

• #2 Kaposi Sarcoma, a Trifecta of Pathogenic Mechanisms

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9140574/

  KSHV infected cells also demonstrate an increased endothelial permeability due to the downregulation and degradation of VE-cadherin. […] Angiopoietin 2 is increased in KS lesions. […] In conclusion, KS is the result of a perfect storm comprised of viral infection, chronic inflammation (B lymphocytes, plasmocytes, monocytes), and oncogenesis (proliferation, immortalization).

• #2 Clinical Manifestations of Kaposi’s Sarcoma

  https://www.cancernetwork.com/view/clinical-manifestations-kaposis-sarcoma

  Oncostatin M, which is produced by macrophages and activated T-lymphocytes, has been shown to have a mitogenic effect on KS cells and thus is an autocrine growth factor for KS. […] Interleukin-6 (IL-6) has also been reported to function as an autocrine growth factor for AIDS-associated KS. […] Long-term KS cell lines demonstrate that these cells express and produce a variety of potent biologic activities. […] These observations indicate that KS cells produce cytokines that support their own growth (autocrine) as well as the growth of other cells (paracrine) and that these cytokines may play a major role in the pathogenesis of AIDS-KS. […] The HIV-1 transactivating (Tat) gene and its product, the Tat protein, have been shown to be important in the pathogenesis of KS. […] The Tat protein may produce the primary growth stimulus for the development of KS cells in HIV-1-infected individuals.

• #2

  https://link.springer.com/article/10.1007/s13555-016-0152-3

  The lesions found in KS are known to contain several cell types, such as infiltrating inflammatory cells, endothelium and spindle cells, which have been postulated to derive from either vascular or lymphatic precursors. […] In HIV-infected individuals, Th1-type cytokines have been suggested to potentiate KSHV activation, which can lead to an increased viral load and a greater likelihood of the development of KS. […] Also, HIV-1-associated trans-activating regulatory (Tat) protein is needed for replication of the HIV virus and is also released from acutely infected T cells. This protein may induce KS by stimulating proangiogenic chemokines, and by enhancing KS cell growth by synergizing with basic fibroblast growth factor (bFGF), which is an essential factor for lesion formation. […] However, the Tat protein is only able to interact with endothelial cells through a RGD motif, which is absent in HIV-2. This may explain why KS is less commonly found in individuals with HIV-2 compared to HIV-1 infection.

• #2 Clinical Manifestations of Kaposi’s Sarcoma

  https://www.cancernetwork.com/view/clinical-manifestations-kaposis-sarcoma

  Activation of the immune system is believed to play a role in the pathogenesis of AIDS-associated KS, as well as classic, endemic, and iatrogenic KS. […] Based on the available data, a hypothetical model for the pathogenesis of AIDS-associated KS has been proposed. […] In summary, HIV-1 infection and immunostimulation, through the effects of their extracellular products, might act together to initiate pathologic molecular and cellular events leading to the proliferation of spindle and mesenchymal cells observed in KS lesions. […] More likely, chronic antigenic stimulation and dysregulation of the immune system are important in the development of AIDS-associated KS, as well as other forms of this disease.

• #2 Kaposi’s Sarcoma-associated Herpesvirus vFLIP Promotes MEndT to Generate Hybrid M/E State for Tumorigenesis | bioRxiv

  https://www.biorxiv.org/content/10.1101/2021.05.04.442576.full

  Finally, KSHV vFLIP was found to play critical roles in KSHV-induced MEndT and oncogenesis. […] Taken together, increasing evidence supports the notion that Kaposi’s sarcoma may arise from KSHV-infected MSCs through MEndT. However, the underlying mechanism remains unclear. […] We found that KSHV promotes incomplete endothelial differentiation of MSCs to generate mesenchymal/endothelial (M/E) hybrid state cells, and the hybrid M/E cells acquired highest tumorigenic properties in vitro and in vivo. […] This finding faithfully recapitulates Kaposi’s sarcoma where proliferating KS spindle cells and the cells that line KS-specific aberrant vessels are also found to exhibit the hybrid M/E state. […] Furthermore, we revealed that KSHV-encoded viral FLICE inhibitory protein (vFLIP) plays a crucial role in promoting MEndT and the generation of M/E state cells. These findings provide a new layer of evidence for MSCs being the cell source of KS spindle cells and reveal novel insight into KS pathogenesis and viral tumorigenesis.

• #2 Pathogenesis of AIDS-Related Kaposi’s Sarcoma

  https://www.cancernetwork.com/view/pathogenesis-aids-related-kaposis-sarcoma

  High levels of IL-6 have been found in patients with KS and may precede the development of the disease in HIV-infected men. […] This striking association has quelled much of the previous controversy regarding the roles of cytomegalovirus, Epstein-Barr virus, human papilloma virus, mycoplasma, and inhaled nitrites in the pathogenesis of KS. […] The authors’ model of the pathogenesis of KS is plausible. In brief, they suggest the following steps in pathogenesis: transformation of normal mesenchymal cells to a „pre-KS” cell by KSHV; proliferation and differentiation of the KS tumor stimulated by the cytokine dysregulation brought on by HIV infection, opportunistic and nonopportunistic infections, and the KS cells themselves; further proliferation of the KS tumor induced by the synergy between cytokines and the HIV tat protein and, in certain clinical settings, by the synergy between cytokines and exogenous steroids; and transformation of KS into a more malignant phenotype as HIV induces greater immunosuppression and as tumors enlarge.

• #2 Kaposi’s sarcoma | Institut Pasteur

  https://www.pasteur.fr/en/medical-center/disease-sheets/kaposi-s-sarcoma

  Kaposis sarcoma (KS) is caused by infection with human herpesvirus-8 (HHV-8). […] The discovery of viral DNA sequences in the skin lesions of HIV-infected patients in 1994 confirmed that human herpesvirus-8 (HHV-8) is associated with Kaposis sarcoma. Since then the virus has been fully sequenced. […] The virus has been found in tumor lesions of all known forms of KS. It has also been demonstrated that HHV-8 infection precedes the emergence of the disease: seroconversion for HHV-8 and detection of viral sequences in peripheral blood lymphocytes a few months or years before the emergence of the clinical disease. […] Much still remains unknown about the pathogenesis of Kaposis sarcoma. While we know that the virus plays an essential role, its interaction with the immune system, especially the inflammatory cytokines, remains poorly understood. And little is known about exactly how KS spreads: what is the precise origin of the tumor cells, are the lesions really cancerous, does the disease involve clonal proliferation (i.e. is it derived from a single cell)? […] These arguments, associated with molecular data, have implicated HHV-8 as the causal agent of Kaposis sarcoma.

• #3 Kaposi Sarcoma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/279734-overview

  Kaposi sarcoma (KS) is an indolent angio-proliferative spindle-cell tumor derived from endothelial and immune cells infected with human herpes virus type 8 (HHV-8; also known as Kaposi sarcoma herpes virus [KSHV]). HHV-8 is identified as the causative agent of KS; it is present in 95-98% of all cases. […] Although all types of KS have in common infection with HHV-8, each has a distinct clinical course. Therefore, it is likely that other factors, such as extent and type of immune suppression, influence the disease. […] The common theme of immune dysregulation is associated with all 4 types of Kaposi sarcoma. Diminished responsiveness of cytotoxic T-lymphocytes is associated with Kaposi sarcoma pathogenesis. […] Restoration of natural killer cell cytoxic effect may explain regression of Kaposi sarcoma in AIDS patients treated with antiretrovirla therapy.

• #3 What Causes Kaposi Sarcoma? | KSHV | HHV8 | American Cancer Society

  https://www.cancer.org/cancer/types/kaposi-sarcoma/causes-risks-prevention/what-causes.html

  Kaposi sarcoma (KS) is caused by infection with a virus called the Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV8). […] In KS, the cells that line blood and lymphatic vessels (called endothelial cells) are infected with KSHV. The virus brings genes into the cells that can cause the cells to divide too much and to live longer than they should. These same genes may cause the endothelial cells to form new blood vessels and may also increase the production of certain chemicals that cause inflammation. These types of changes may eventually turn them into cancer cells. […] KSHV infection is needed to cause KS, but in most cases infection with KSHV alone does not lead to KS. Most people who develop KS have the KSHV and also have a weakened immune system, due to HIV infection, organ transplant, being older, or some other factor.

• #3 Kaposi’s sarcoma-associated herpesvirus – Wikipedia

  https://en.wikipedia.org/wiki/Kaposi%27s_sarcoma-associated_herpesvirus

  It has been shown that both protein coding genes such as LANA and noncoding genes (microRNAs) encoded in KLAR are important for KSHV associated tumorigenesis. […] These observations represent a novel mechanism that may be important for KSHV tumorigenesis and angiogenesis, a hallmark of KS. […] Various signals such as inflammation may provoke the virus to enter into lytic replication. The primary viral protein responsible for the switch between latent and lytic replication is known as the ORF50 Replication Transactivation Activator (RTA). […] During lytic replication, it is believed that the virus genome is replicated as a continuous linear molecule off of an episome (so-called rolling circle model). […] Thus, whereas KSHV genome is circular in the nucleus of latently infected cells, it is packaged into infectious viruses as a linear molecule.

• #3 Kaposi’s sarcoma pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Kaposi%27s_sarcoma_pathophysiology

  During the latent period, HHV-8 will express a viral latency-associated nuclear antigen (LANA-1) that acts as transcriptional modulator. […] The functions of HHV-8 viral latency-associated nuclear antigen (LANA-1) include: A tethering molecule that stabilize the viral DNA to the cellular chromosome, An inhibitor of p53 tumor suppressor protein, An inhibitor of retinoblastoma (Rb) tumor suppressor protein, A suppressor of the viral lytic phase of replication.

• #3 Kaposi Sarcoma: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/279734-overview

  The current working hypothesis is that HHV-8 must be present for the disease to develop. […] Factors that are thought to contribute to the development of Kaposi sarcoma in individuals infected with HHV-8 and HIV include an abnormal cytokine milieu associated with HIV infection, and involving the following angiogenic cytokines: Interleukin-1 (IL-1) beta, Basic fibroblast growth factor (bFGF), Acidic fibroblast growth factor, Endothelial growth factor, Vascular endothelial growth factor (VEGF). […] Oncostatin M, IL-1, IL-6, fibroblast growth factor, tumor necrosis factor (TNF), and the HIV-tat protein all of which originate from HIV-infected T cells act as costimulants for Kaposi sarcoma cells. […] A specific viral gene, ORF74, encodes for a G-protein coupled receptor that causes production of VEGF and other angiogenic mediators.

• #3 Kaposi Sarcoma, a Trifecta of Pathogenic Mechanisms

  https://www.mdpi.com/2075-4418/12/5/1242

  v-IL6, a protein expressed both during the latent (at lower but functional levels) and lytic viral phase of KSHV, plays an important role in KS genesis through angiogenesis, cell proliferation and invasion via downregulation of caveolin 1 (CAV1). […] vBCL-2 serves as both a way to extend cell survival via apoptosis inhibition and also evade the autophagic innate system. […] vCyclin accelerates cell-cycle progression and also promotes apoptosis in cells with increased levels of CDK6. […] K1 plays an important role in lytic replication, cellular survival and immortalization of human endothelial cells. […] Kaposi’s sarcoma development is somewhat different (but not unique). It can promote VEGF-A secretion in normoxic conditions by several methods by way of KSHV proteins. […] KSHV infected cells also demonstrate an increased endothelial permeability due to the downregulation and degradation of VE-cadherin.

• #4

  https://www.jci.org/articles/view/40567

  The first three genes are under the control of a single promoter (the LANA promoter, or LTc), which generates a series of coterminal mRNAs via differential splicing. […] LANA very likely makes additional, more direct biochemical contributions to tumorigenesis, since it has also been shown to bind and (partially) inhibit the cellular tumor suppressor genes p53 and Rb. […] Together, these activities could inhibit apoptosis and thus extend spindle cell survival, and also stimulate spindle cell proliferation. […] The role of the adjacent v-FLIP gene, which encodes a homolog of known cellular FLIPs, is much better understood. […] v-FLIPs prosurvival activity is linked to its ability to activate the transcription factor NF-B. […] The net result is activation of a large program of cytokine and chemokine expression.

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