Increased tumour angiogenesis in SOX11‐positive mantle cell lymphoma

Petrakis, Georgios; Veloza, Luis; Clot, Guillem; Giné, Eva; González-Farré, Blanca; Navarro, Alba; Beà, Sı́lvia; Martı́nez, Antonio; López‐Guillermo, Armando; Amador, Virginia; Ribera‐Cortada, Inmaculada; Campo, Elı́as

doi:10.1111/his.13935

Cited by 15 publications

(6 citation statements)

References 36 publications

(120 reference statements)

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“… 30 The relationship between angiogenesis and SOX11 expression has been revealed, and SOX11 was demonstrated to elevate an angiogenic phenotype in primary MCL. 31 Interestingly, our research verified that CCND1 knockdown repressed USP9X overexpression-mediated SOX11 protein level, suggesting that USP9X downregulated CCND1-mediated SOX11 expression in MCL cells. USP9X overexpression could promote WP1130-mediated USP9X, CCND1, and SOX11 protein levels, indicating that USP9X exerts its function by deubiquitinating Cyclin D1 and/or SOX11.…”

Section: Discussionsupporting

confidence: 64%

Usp9x Increased Tumor Angiogenesis in Mantle Cell Lymphoma by Upregulation of Ccnd1- Mediated Sox11

Huang¹,

Liao²,

Wang³

et al. 2022

Mediterr J Hematol Infect Dis

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Mantle cell lymphoma (MCL) is an aggressive lymphoid malignancy with a poor prognosis. Ubiquitin-specific peptidase 9, X-linked (USP9X), has been found to be associated with multiple physiological pathways and regulate a variety of cellular activities. In this study, we explored the role of USP9X in MCL in vitro and in vivo. USP9X was verified to be increased in peripheral blood mononuclear cells (PBMCs) of MCL patients and MCL cells. Moreover, USP9X overexpression and knockdown were performed in MCL cells. We proved that USP9X overexpression promoted proliferation and cell cycle, and suppressed cell apoptosis in MCL cells. Unregulation of angiogenesis and cell migrate were induced by USP9X overexpression in MCL cells. However, USP9X knockdown showed opposite effects. In addition, USP9X was discovered to decrease Cyclin D1 (CCND1)-mediated SOX11 expression in MCL cells. We demonstrated that SOX11 overexpression reversed USP9X knockdown-mediated angiogenesis in MCL cells. Besides, tumor formation was inhibited by USP9X knockdown in mice in vivo. In conclusion, these results revealed that USP9X promoted tumor angiogenesis in MCL via increasing CCND1- mediated SOX11.

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Section: Discussionsupporting

confidence: 64%

Usp9x Increased Tumor Angiogenesis in Mantle Cell Lymphoma by Upregulation of Ccnd1- Mediated Sox11

Huang¹,

Liao²,

Wang³

et al. 2022

Mediterr J Hematol Infect Dis

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“…Recent studies identiﬁed a subgroup of MCL that has a more indolent behavior with a clinical presentation as leukemic disease, exhibiting minimal LN distribution and a frequent splenomegaly. These tumors also overexpress cyclin D1 but lack expression of the sex determining region-Y-box11 (SOX11), a TF specifically expressed in conventional MCL and associated with an aggressive and angiogenic phenotype ( 232 ). These results have been confirmed in MCL patient samples by using immunohistochemistry, demonstrating a correlation between an increased MVD and high levels of SOX11 expression ( 233 ).…”

Section: B Cell Lymphoma-induced Vascular Changes Are Dependent On Thmentioning

confidence: 99%

Angiogenesis in Lymph Nodes Is a Critical Regulator of Immune Response and Lymphoma Growth

2020

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Tumor-induced remodeling of the microenvironment in lymph nodes (LNs) includes the formation of blood vessels, which goes beyond the regulation of metabolism, and shaping a survival niche for tumor cells. In contrast to solid tumors, which primarily rely on neo-angiogenesis, hematopoietic malignancies usually grow within pre-vascularized autochthonous niches in secondary lymphatic organs or the bone marrow. The mechanisms of vascular remodeling in expanding LNs during infection-induced responses have been studied in more detail; in contrast, insights into the conditions of lymphoma growth and lodging remain enigmatic. Based on previous murine studies and clinical trials in human, we conclude that there is not a universal LN-specific angiogenic program applicable. Instead, signaling pathways that are tightly connected to autochthonous and infiltrating cell types contribute variably to LN vascular expansion. Inflammation related angiogenesis within LNs relies on dendritic cell derived pro-inflammatory cytokines stimulating vascular endothelial growth factor-A (VEGF-A) expression in fibroblastic reticular cells, which in turn triggers vessel growth. In high-grade B cell lymphoma, angiogenesis correlates with poor prognosis. Lymphoma cells immigrate and grow in LNs and provide pro-angiogenic growth factors themselves. In contrast to infectious stimuli that impact on LN vasculature, they do not trigger the typical inflammatory and hypoxia-related stroma-remodeling cascade. Blood vessels in LNs are unique in selective recruitment of lymphocytes via high endothelial venules (HEVs). The dissemination routes of neoplastic lymphocytes are usually disease stage dependent. Early seeding via the blood stream requires the expression of the homeostatic chemokine receptor CCR7 and of L-selectin, both cooperate to facilitate transmigration of tumor and also of protective tumor-reactive lymphocytes via HEV structures. In this view, the HEV route is not only relevant for lymphoma cell homing, but also for a continuous immunosurveillance. We envision that HEV functional and structural alterations during lymphomagenesis are not only key to vascular remodeling, but also impact on tumor cell accessibility when targeted by T cell–mediated immunotherapies.

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“…[4][5][6][7] SOX11 contributes to MCL oncogenesis and aggressive behavior through several mechanisms that include blocking the B-cell differentiation program, activation of the B-cell receptor (BCR) signaling pathway, and regulating different interactions between tumor cells and the microenvironment. [8][9][10][11][12][13][14] Some studies have shown that the number of CD4 1 T cells in peripheral blood and tumor infiltrate of MCL positively correlate with low proliferation, indolent disease, and favorable outcome. 15,16 On the other hand, CD40/CD40L interactions seem to promote MCL proliferation and survival.…”

Section: Introductionmentioning

confidence: 99%

SOX11, CD70, and Treg cells configure the tumor immune microenvironment of aggressive mantle cell lymphoma

Balsas

Veloza

Clot

et al. 2021

Blood

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Mantle cell lymphoma (MCL) is a mature B-cell neoplasm with a heterogeneous clinical and biological behavior. SOX11 oncogenic expression contributes to the aggressiveness of these tumors by different mechanisms including tumor and stromal cell interactions. However, the precise composition of the immune cell microenvironment of MCL, its possible relationship to SOX11 expression, and how it may contribute to tumor behavior is not well known. Here, we performed an integrative transcriptome analysis of 730 immune-related genes combined with the immune cell phenotype analysis by immunohistochemistry in SOX11+ and SOX11- primary nodal MCL cases and non-neoplastic reactive lymph nodes (RLN). SOX11+ MCL had a significant lower T-cell intratumoral infiltration compared to negative cases. A reduced expression of MHCI/II-like and T-cell costimulation and signaling activation related transcripts was significantly associated with poor clinical outcome. Moreover, we identified CD70 as a SOX11 direct target gene, whose overexpression was induced in SOX11+ but not SOX11- tumor cells by CD40L in vitro. CD70 was overexpressed in primary SOX11+ MCL and it was associated with an immune unbalance of the tumor microenvironment characterized by increased number of effector Treg cell infiltration, higher proliferation, and aggressive clinical course. CD27 was expressed with moderate to strong intensity in 76% of cases. Overall, our results suggest that SOX11 expression in MCL is associated with an immunosuppressive microenvironment characterized by CD70 overexpression in tumor cells, increased Treg cell infiltration and downmodulation of antigen-processing and -presentation and T-cell activation that could promote MCL progression and represent a potential target for tailored therapies.

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Increased tumour angiogenesis in SOX11‐positive mantle cell lymphoma

Cited by 15 publications

References 36 publications

Usp9x Increased Tumor Angiogenesis in Mantle Cell Lymphoma by Upregulation of Ccnd1- Mediated Sox11

Usp9x Increased Tumor Angiogenesis in Mantle Cell Lymphoma by Upregulation of Ccnd1- Mediated Sox11

Angiogenesis in Lymph Nodes Is a Critical Regulator of Immune Response and Lymphoma Growth

SOX11, CD70, and Treg cells configure the tumor immune microenvironment of aggressive mantle cell lymphoma

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