Shaping of the tumor microenvironment: Stromal cells and vessels

Blonska, Marzenna; Agarwal, Nitin; Vega, Francisco

doi:10.1016/j.semcancer.2015.03.002

Cited by 44 publications

(40 citation statements)

References 126 publications

(138 reference statements)

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“…15,16,43 Here, we provide evidence for the presence of noncanonical GLI1 transcriptional activation mediated by IKKb. Using in vitro stromal systems and in vivo models of DLBCL, we found that inhibiting IKKb-mediated NF-kB activation and GLI1 synergistically decreased DLBCL cell viability, supporting a novel therapeutic approach for DLBCL based on concomitant inhibition of NF-kB and GLI1.…”

Section: Discussionmentioning

confidence: 59%

Active IKKβ promotes the stability of GLI1 oncogene in diffuse large B-cell lymphoma

Agarwal¹,

Kim²,

Kunkalla³

et al. 2016

Blood

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• IKKb, independently of NF-kB, regulates the stability and transcriptional activity of GLI1 oncogene.• Combined inhibition of IKKb and GLI1 activities synergistically decreases DLBCL cell viability in vivo and in vitro.GLI1 oncogene has been implicated in the pathobiology of several neoplasms including diffuse large B-cell lymphoma (DLBCL). However, mechanisms underlying GLI1-increased activity in DLBCL are poorly characterized. Herein, we demonstrate that IKKb phosphorylates GLI1 in DLBCL. IKKb activation increased GLI1 protein levels and transcriptional activity, whereas IKKb silencing decreased GLI1 levels and transcriptional activity. Tumor necrosis factor-a (TNFa) mediated IKKb activation-impaired GLI1 binding with the E3 ubiquitin ligase-ITCH, leading to decreased K48-linked ubiquitination/ degradation of GLI1. We found 8 IKKb-dependent phosphorylation sites that mediate GLI1 stability. Mutating or deleting these residues facilitated GLI1-ITCH interaction and decreased the protective effect of TNFa on GLI1 stability. IKKb-GLI1 crosstalk is significant because combined inhibition of both molecules resulted in synergistic suppression of DLBCL viability in vivo and in vitro. By linking IKKb-mediated nuclear factor-kB activity with GLI1, we identified a crosstalk between these 2 pathways that can inform the design of novel therapeutic strategies in DLBCL. (Blood. 2016;127(5):605-615)

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Section: Discussionmentioning

confidence: 59%

Active IKKβ promotes the stability of GLI1 oncogene in diffuse large B-cell lymphoma

Agarwal¹,

Kim²,

Kunkalla³

et al. 2016

Blood

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“…4 and 5) is thus a result of neutralization of heparanase contributed by the tumor microenvironment. The microenvironment of B-cell lymphomas contains variable numbers of immune cells (i.e., T-cells, macrophages, neutrophils), stromal cells (i.e., fibroblasts), and endothelial cells (17,32,33), many of which have been reported to express heparanase (34,35). The significance of the tumor microenvironment in tumorigenesis is well documented and accepted (36).…”

Section: Discussionmentioning

confidence: 99%

“…The significance of the tumor microenvironment in tumorigenesis is well documented and accepted (36). In B lymphomas, a complex cross-talk between the lymphoma cells and their respective microenvironment is bidirectional, and multiple secreted factors and cell surface molecules contribute to the activation of signaling pathways in both the lymphoma and stromal cells (32), many of which are targets for the development of lymphoma therapeutics (37). Heparanase activity is thought to release a multitude of HS-bound cytokines, chemokines, and growth-promoting factors sequestered in the ECM and convert them into bioavailable and biologically active mediators that promote cell proliferation, survival, and motility (38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Weissmann¹,

Arvatz²,

Horowitz

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

104

140

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Heparanase is an endoglycosidase that cleaves heparan sulfate side chains of proteoglycans, resulting in disassembly of the extracellular matrix underlying endothelial and epithelial cells and associating with enhanced cell invasion and metastasis. Heparanase expression is induced in carcinomas and sarcomas, often associating with enhanced tumor metastasis and poor prognosis. In contrast, the function of heparanase in hematological malignancies (except myeloma) was not investigated in depth. Here, we provide evidence that heparanase is expressed by human follicular and diffused non-Hodgkin's B-lymphomas, and that heparanase inhibitors restrain the growth of tumor xenografts produced by lymphoma cell lines. Furthermore, we describe, for the first time to our knowledge, the development and characterization of heparanaseneutralizing monoclonal antibodies that inhibit cell invasion and tumor metastasis, the hallmark of heparanase activity. Using luciferase-labeled Raji lymphoma cells, we show that the heparanase-neutralizing monoclonal antibodies profoundly inhibit tumor load in the mouse bones, associating with reduced cell proliferation and angiogenesis. Notably, we found that Raji cells lack intrinsic heparanase activity, but tumor xenografts produced by this cell line exhibit typical heparanase activity, likely contributed by host cells composing the tumor microenvironment. Thus, the neutralizing monoclonal antibodies attenuate lymphoma growth by targeting heparanase in the tumor microenvironment.heparanase | lymphoma | neutralizing antibody | tumor growth | metastasis H eparanase is an endo-β-D-glucuronidase capable of cleaving heparan sulfate (HS) side chains at a limited number of sites, releasing saccharide products with appreciable size (4-7 kDa) and biological potency. Enzymatic degradation of HS leads to disassembly of the extracellular matrix (ECM) and correlates with the metastatic potential of tumor-derived cells, attributed to enhanced cell dissemination as a consequence of HS cleavage and remodeling of the ECM and basement membrane underlying epithelial and endothelial cells (1, 2). Heparanase expression is induced in human cancer, most often associating with reduced patients' survival postoperation, increased tumor metastasis, and higher vessel density (3-5). In addition, heparanase up-regulation is associated with tumors larger in size (3, 5). Likewise, heparanase over-expression enhanced (6, 7), whereas local delivery of anti-heparanase siRNA inhibited (8), the growth of tumor xenografts. These results imply that heparanase function is not limited to tumor metastasis but is engaged in progression of the primary lesion, thus critically supporting the intimate involvement of heparanase in tumor progression and encouraging the development of heparanase inhibitors as anticancer therapeutics (9-12). As a consequence, heparanase inhibitors are currently evaluated in phase 1 clinical trials (13).Heparanase activity is similarly implicated in the progression of multiple myeloma (14-16), but its significan...

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“…Furthermore, a previous study revealed that chemokines and adhesion molecules, which are components of the tumor microenvironment, contribute to the migration and homing of malignant B lymphocytes (19); these molecules include L-selectin, C-X-C chemokine receptor type 4, lymphocyte function-associated antigen 1, C-C chemokine receptor type (CCR)7 and CCR2 (19). Additionally, the microenvironment is crucial for the survival of malignant T and B lymphocytes (27). In recent years, the interaction between the tumor microenvironment and MSCs, and the functions in tumor growth and progression, have been identified (18).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have demonstrated that the interaction between cancer cells and the stromal cells of the tumor microenvironment is required for the survival and localization of cancer cells (27)(28)(29). Recently, targeted treatments based on cytokines and adhesion molecules have been investigated, leading to improvements in the treatment of tumors and inhibition of tumor metastasis (30).…”

Section: Discussionmentioning

confidence: 99%

Primary non‑Hodgkin lymphoma of the right femur and subsequent metastasis to the left femur: A case report and literature review

2018

Oncol Lett

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Abstract. Non-Hodgkin lymphoma of the bone is rare and typically causes an extensive bone lesion. The present study describes a case of diffuse large B-cell primary non-Hodgkin lymphoma of the bone, which occurred in the right femur, and was initially treated with surgery and chemotherapy. Following a 7-year period of complete remission, a new, similar lesion was identified in the left femur. With both lesions, there was no accompanying destruction of any other bones or organ involvement. Metastasis of PLB to the contralateral side is extremely rare and, to the best of our knowledge, this is the first report of this particular presentation in China or worldwide. We hypothesized that the present situation arose due to mechanisms involving the tumor microenvironment, circulating tumor cells, lymphocyte homing and self-seeding. The present report describes the case in detail, and discusses the possible underlying mechanisms and their potential contribution to the treatment of non-Hodgkin lymphoma, as well as the prevention of metastasis and recurrence, which may be of considerable clinical significance.

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Shaping of the tumor microenvironment: Stromal cells and vessels

Cited by 44 publications

References 126 publications

Active IKKβ promotes the stability of GLI1 oncogene in diffuse large B-cell lymphoma

Active IKKβ promotes the stability of GLI1 oncogene in diffuse large B-cell lymphoma

Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis

Primary non‑Hodgkin lymphoma of the right femur and subsequent metastasis to the left femur: A case report and literature review

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