Bone marrow angiogenesis in multiple myeloma and its correlation with clinicopathological factors

Rana, Chanchal; Sharma, Seema; Agrawal, Vinita; Singh, Uttam

doi:10.1007/s00277-010-0919-z

Cited by 23 publications

(13 citation statements)

References 10 publications

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“…Galectin-3 has been shown to facilitate, and Gal-3C to inhibit VEGF-mediated angiogenesis [49]. Importantly, increased angiogenesis has been found to be indicative of poor prognosis in MM patients [45], [50], [51]. Thus, we postulated that the effects of Gal-3C in vivo could be at least partly due to inhibition of angiogenesis induced by the engrafted U266 cells, and tested this postulate using in vitro HUVEC migration and angiogenesis assays.…”

Section: Discussionmentioning

confidence: 99%

Galectin-3C Inhibits Tumor Growth and Increases the Anticancer Activity of Bortezomib in a Murine Model of Human Multiple Myeloma

et al. 2011

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Galectin-3 is a human lectin involved in many cellular processes including differentiation, apoptosis, angiogenesis, neoplastic transformation, and metastasis. We evaluated galectin-3C, an N-terminally truncated form of galectin-3 that is thought to act as a dominant negative inhibitor, as a potential treatment for multiple myeloma (MM). Galectin-3 was expressed at varying levels by all 9 human MM cell lines tested. In vitro galectin-3C exhibited modest anti-proliferative effects on MM cells and inhibited chemotaxis and invasion of U266 MM cells induced by stromal cell-derived factor (SDF)-1α. Galectin-3C facilitated the anticancer activity of bortezomib, a proteasome inhibitor approved by the FDA for MM treatment. Galectin-3C and bortezomib also synergistically inhibited MM-induced angiogenesis activity in vitro. Delivery of galectin-3C intravenously via an osmotic pump in a subcutaneous U266 cell NOD/SCID mouse model of MM significantly inhibited tumor growth. The average tumor volume of bortezomib-treated animals was 19.6% and of galectin-3C treated animals was 13.5% of the average volume of the untreated controls at day 35. The maximal effect was obtained with the combination of galectin-3C with bortezomib that afforded a reduction of 94% in the mean tumor volume compared to the untreated controls at day 35. In conclusion, this is the first study to show that inhibition of galectin-3 is efficacious in a murine model of human MM. Our results demonstrated that galectin-3C alone was efficacious in a xenograft mouse model of human MM, and that it enhanced the anti-tumor activity of bortezomib in vitro and in vivo. These data provide the rationale for continued testing of galectin-3C towards initiation of clinical trials for treatment of MM.

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Section: Discussionmentioning

confidence: 99%

Galectin-3C Inhibits Tumor Growth and Increases the Anticancer Activity of Bortezomib in a Murine Model of Human Multiple Myeloma

et al. 2011

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“…38 In MM patients, bone-marrow angiogenesis, manifested by higher microvessel density, correlates with disease stage and poor prognosis. 46,47 MM cells induce angiogenesis directly through the production of angiogenic factors (eg, VEGF) 19 and interactions with the microenvironment (eg, endothelial cells, stromal cells, and osteoclasts). 38 VEGF and bone-marrow angiogenesis support the survival, proliferation, and migration of MM cells while contributing to drug resistance and MM-associated bone disease.…”

Section: Discussionmentioning

confidence: 99%

Disruption of Src function potentiates Chk1-inhibitor–induced apoptosis in human multiple myeloma cells in vitro and in vivo

Dai

Chen

Shah

et al. 2011

Blood

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IntroductionMultiple myeloma (MM) is a neoplastic disorder of mature, differentiated B lymphocytes. Whereas recent insights into MM molecular pathogenesis prompted the introduction of effective new agents, including the proteasome inhibitor bortezomib and the immunomodulatory agents thalidomide and lenalidomide, MM remains largely incurable 1 and new strategies are clearly needed.DNA-damage checkpoints halt cell-cycle progression after extrinsic DNA damage (eg, by genotoxic agents or radiation) or intrinsic DNA-replication stress during the undisturbed cell cycle, permitting DNA-repair machinery initiation or DNA-replication block circumvention. 2 Checkpoint responses are initiated by ATM (Ataxia telangiectasia mutated) and ATR (Ataxia telangiectasia and Rad3-related), which induce checkpoint kinases (Chk1 and Chk2), thus disabling Cdk1/p34 cdc2 or Cdk2 by preventing dephosphorylation at inhibitory sites (T14/Y15) via inhibition/degradation of Cdc25 phosphatases, resulting in cell-cycle arrest. Genomic instability and defective DNA-damage checkpoints are characteristic of diverse human cancers, including MM. 3 Chk1 has a critical role in the DNA-damage-response network. 2 Moreover, novel Chk1 functions in the DNA-replication checkpoint, the mitoticspindle checkpoint, and DNA repair have been identified, 2,4 stimulating clinical development of multiple Chk1 inhibitors, including UCN-01 (Kyowa), AZD7762 (AstraZeneca), LY2603618 (Lilly), SCH900776 (Schering-Plough), and PF-00477736 (Pfizer). Whereas these efforts have focused on chemotherapy or radiation sensitization, 2,5,6 recent evidence implicating Chk1 in normal cell-cycle checkpoints (eg, the DNA replication checkpoint) suggests alternative therapeutic strategies.We previously reported that Chk1 inhibitors (eg, UCN-01 or more specific Chk1 inhibitors) activate extracellular signalregulated kinase 1/2 (ERK1/2) in human MM and leukemia cells, while blockade of this event by MEK1/2 (mitogen-activated protein kinase [MAPK]/ERK kinase 1/2) inhibitor dramatically induces apoptosis. 7,8 Furthermore, interruption of Ras function by farnesyltransferase inhibitors 9,10 or statins 11 acted similarly. Because Src plays an important role in Ras 3 ERK1/2 signaling activation, 12 the possibility that Src may be involved in Chk1-inhibitor-mediated ERK1/2 activation arose. Src family kinases (SFKs) are up-regulated/activated in multiple human tumors. 13 Src itself has been implicated in transformation, survival, proliferation, adhesion, migration, invasion, 12,13 and angiogenesis. 14 Src is generally activated by receptor tyrosine kinases or integrin-related kinases (eg, focal adhesion kinase [FAK] 16 Recently, Src inhibitors (eg, BMS354825) were shown to inhibit angiogenesis and the proliferative/survival effects of growth factors, including vascular endothelial growth factor (VEGF) and The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact,...

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“…Increased bone marrow microcirculation is associated with adverse outcome in patients with multiple myeloma (4,5) as well as SMM (6), and angiogenesis is directly linked to the development of multiple myeloma-related bone disease (7,8). Furthermore, patients in remission after therapy showed a significantly decreased MVD compared with those with residual disease (9)(10)(11). In most of these studies, histologic evaluation of bone marrow biopsies was performed to quantify angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Assessment of Antiangiogenic Treatment Effects in Multiple Myeloma

Merz

Ritsch

Kunz

et al. 2015

Clinical Cancer Research

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Purpose: To noninvasively assess bone marrow microcirculation before and after therapy in patients with newly diagnosed multiple myeloma with dynamic contrast-enhanced MRI (DCE-MRI).Experimental Design: Ninety-six patients received DCE-MRI before and after primary treatment for newly diagnosed multiple myeloma. For the 91 evaluable patients, treatment consisted of high-dose therapy (HDT) with autologous stem cell transplantation (ASCT) in 82 patients and chemotherapy without ASCT in 9 patients. In addition, 33 healthy volunteers were imaged as the control group. Analysis of DCE-MRI was performed according to the two-compartment model by Brix to quantify amplitude A (associated with blood volume) and exchange rate constant k ep (reflecting vessel permeability and perfusion).Results: Nonresponders showed significantly higher A-values before the start of therapy compared with responders (P ¼ 0.02). In both responders and nonresponders to therapy, A-values dropped significantly (P ¼ 0.004 and <0.001, respectively) after primary therapy, whereas lower values for k ep were found only in responders (P < 0.001). Depth of remission was significantly correlated to decreased bone marrow microcirculation: Patients in near complete response (nCR) or complete remission (CR) after treatment showed significantly lower values for A compared with patients not achieving nCRþCR. The application of HDT or novel agents had no significant effect on DCE-MRI parameters after therapy, although patients treated with novel agents more often achieved nCRþCR (42%/12.5%; P < 0.002). Higher k ep -values at second MRI were positively correlated to shorter overall survival (HR 3.53; 95% confidence intervals, 1.21-10.33; P ¼ 0.02).Conclusion: Parameters from DCE-MRI are correlated to remission after primary therapy and outcome in newly diagnosed multiple myeloma.

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Bone marrow angiogenesis in multiple myeloma and its correlation with clinicopathological factors

Cited by 23 publications

References 10 publications

Galectin-3C Inhibits Tumor Growth and Increases the Anticancer Activity of Bortezomib in a Murine Model of Human Multiple Myeloma

Galectin-3C Inhibits Tumor Growth and Increases the Anticancer Activity of Bortezomib in a Murine Model of Human Multiple Myeloma

Disruption of Src function potentiates Chk1-inhibitor–induced apoptosis in human multiple myeloma cells in vitro and in vivo

Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Assessment of Antiangiogenic Treatment Effects in Multiple Myeloma

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