Angiogenesis-Related Cytokines, RANKL, and Osteoprotegerin in Multiple Myeloma Patients in relation to Clinical Features and Response to Treatment

Sfiridaki, Katerina; Pappa, Constantina A.; Tsirakis, George; Kanellou, Peggy; Kaparou, Maria; Stratinaki, Maria; Sakellaris, George; Kontakis, George; Alexandrakis, Michael G.

doi:10.1155/2011/867576

Cited by 20 publications

(17 citation statements)

References 38 publications

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“…Bone marrow angiogenesis is an important process contributing to disease development and progression (33). Serum levels of RANKL and the RANKL/OPG ratio have been found to significantly correlate with markers of angiogenesis, including VEGF, in patients with multiple myeloma (34). In addition, in wild-type mice and using cultured human umbilical vein epithelial cells, RANKL was shown to promote vascular permeability and angiogenesis through stimulation of endothelial nitric oxide synthase; TNF receptor-associated factor 6 (TRAF6) and PI3K Akt were essential to this process (35).…”

Section: Metastasis-initiating Function: Angiogenesis Invasion and Cmentioning

confidence: 99%

Role of the RANK/RANKL Pathway in Multiple Myeloma

Raje

Bhatta

Terpos

2019

Clinical Cancer Research

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Receptor activator of nuclear factor-kappa B (RANK) and its ligand, RANKL, are expressed in a variety of tissues throughout the body; their primary role is in the regulation of bone remodeling and development of the immune system. Consistent with these functions, evidence exists for a role of RANK/RANKL in all stages of tumorigenesis, from cell proliferation and carcinogenesis to epithelial-mesenchymal transition to neoangiogenesis and intravasation to metastasis to bone resorption and tumor growth in bone. Results from current studies also point to a role of RANK/RANKL signaling in patients with multiple myeloma, who have increased serum levels of soluble RANKL and an imbalance in RANKL and osteoprotegerin. Current therapies for patients with multiple myeloma demonstrate that RANKL may be released by tumor cells or osteoprogenitor cells. This article will review currently available evidence supporting a role for RANK/RANKL signaling in tumorigenesis, with a focus on patients with multiple myeloma.

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Section: Metastasis-initiating Function: Angiogenesis Invasion and Cmentioning

confidence: 99%

Role of the RANK/RANKL Pathway in Multiple Myeloma

Raje

Bhatta

Terpos

2019

Clinical Cancer Research

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“…The quantitation of microvessel density in histologic specimens of invasive breast cancer, for example, has provided an indication of the risk of metastasis [41]. A positive association between tumor angiogenesis and the risk of metastasis, tumor recurrence, or death has also been reported with regard to breast cancers and other types of tumors [42–44]. A high microvessel density may be a successful predictor of metastatic risk.…”

Section: Angiogenesis In Clinical Applicationsmentioning

confidence: 99%

Angiogenesis and Its Therapeutic Opportunities

Yoo

Kwon

2013

Mediators of Inflammation

198

133

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Angiogenesis plays critical roles in human physiology that range from reproduction and fetal growth to wound healing and tissue repair. The sophisticated multistep process is tightly regulated in a spatial and temporal manner by “on-off switch signals” between angiogenic factors, extracellular matrix components, and endothelial cells. Uncontrolled angiogenesis may lead to several angiogenic disorders, including vascular insufficiency (myocardial or critical limb ischemia) and vascular overgrowth (hemangiomas, vascularized tumors, and retinopathies). Thus, numerous therapeutic opportunities can be envisaged through the successful understanding and subsequent manipulation of angiogenesis. Here, we review the clinical implications of angiogenesis and discuss pro- and antiangiogenic agents that offer potential therapy for cancer and other angiogenic diseases.

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“…Previous data reported an inhibitory role of RANKL in angiogenesis (14,15), which could explain its lower serum levels in patients compared to controls. To evaluate angiogenesis, we administered serum VEGF, which is a key angiogenic factor mediating neo-vascularization and could act as a surrogate marker of tumor angiogenesis (40).…”

Section: Discussionmentioning

confidence: 96%

“…In addition to the known role of RANKL in the skeletal and immune systems (13), recent studies also reported a role of RANKL in angiogenesis. Certain authors support an inhibitory role of RANKL (14,15), whereas others showed a stimulating action on angiogenesis (16). Contrary to RANKL, VEGF is known as a potent mitogen angiogenic factor and is one of the most important molecules involved in the vascularization of bone tissue (17), thus its serum levels are considered an index of angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Bone metastases in gastric cancer follow a RANKL-independent mechanism

et al. 2013

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Abstract. Gastric cancer is one of the most common and lethal malignancies worldwide. Bone metastases in gastric cancer are less common than in other solid tumors, but when they occur the prognosis is generally poor. Increased osteoclastogenesis and osteoclast activity are common features in bone metastases caused by different osteotropic cancer. We investigated osteoclastogenesis and its mechanisms in gastric cancer by enrolling 31 newly diagnosed gastric cancer patients and 45 healthy controls. We studied in vitro osteoclastogenesis in the peripheral blood mononuclear cell cultures of patients and controls, showing spontaneous osteoclastogenesis for half of the patients. This osteoclastogenesis was RANKL-and TNF-α-independent. We analyzed primary tumor and bone metastatic tissues of gastric cancer for the expression of genes involved in osteoclastogenesis. The expression of transforming growth factor-β (TGF-β), osteoprotegerin (OPG), IL-7 and dickkopf-1 (DKK-1) was higher in primary tumors than in bone metastases. RANKL was not detectable in primary tumor or in bone metastatic tissue. The serum RANKL level was significantly higher in healthy controls than in patients, and it was not related to osteoclastogenesis, thereby suggesting that RANKL is not involved in the bone metastatic mechanisms in gastric cancer. We hypothesized a role of RANKL in angiogenesis, thus we compared the serum levels of RANKL to those of VEGF, since VEGF is directly related to angiogenesis. Different from RANKL, the VEGF serum levels were higher in gastric patients than in controls, suggesting a block of the angiogenesis inhibition due to RANKL. RANKL and VEGF serum levels were not predictive of overall survival in our cohort of gastric patients.

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Angiogenesis-Related Cytokines, RANKL, and Osteoprotegerin in Multiple Myeloma Patients in relation to Clinical Features and Response to Treatment

Cited by 20 publications

References 38 publications

Role of the RANK/RANKL Pathway in Multiple Myeloma

Role of the RANK/RANKL Pathway in Multiple Myeloma

Angiogenesis and Its Therapeutic Opportunities

Bone metastases in gastric cancer follow a RANKL-independent mechanism

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