Dual effects of macrophage inflammatory protein-1α on osteolysis and tumor burden in the murine 5TGM1 model of myeloma bone disease

University of Texas at San Antonio, San Antonio, Texas, United States
Blood (Impact Factor: 10.45). 08/2003; 102(1):311-9. DOI: 10.1182/blood-2002-12-3905
Source: PubMed


Recent data have implicated macrophage inflammatory protein-1alpha (MIP-1alpha) in multiple myeloma (MM)-associated osteolysis. However, it is unclear whether the chemokine's effects are direct, to enhance osteolysis, or indirect and mediated through a reduction in tumor burden, or both. It is also unclear whether MIP-1alpha requires other factors such as receptor activator of nuclear factor-kappaB ligand (RANKL) for its effects on bone. In murine 5TGM1 (Radl) myeloma-bearing mice, administration of neutralizing anti-MIP-1alpha antibodies reduced tumor load assessed by monoclonal paraprotein titers, prevented splenomegaly, limited development of osteolytic lesions, and concomitantly reduced tumor growth in bone. To determine the effects of MIP-1alpha on bone in vivo, Chinese hamster ovary (CHO) cells secreting human MIP-1alpha (CHO/MIP-1alpha) were inoculated into athymic mice. Mice bearing intramuscular CHO/MIP-1alpha tumors developed lytic lesions at distant skeletal sites, which occurred earlier and were larger than those in mice with CHO/empty vector (EV) tumors. When experimental metastases were induced via intracardiac inoculation, mice bearing CHO/MIP-1alpha tumors developed hypercalcemia and significantly more osteolytic lesions than mice bearing CHO/EV tumors, with intramedullary CHO/MIP-1alpha tumors associated with significantly more tartrate-resistant acid phosphatase-positive (TRAP+) osteoclasts. Injection of recombinant MIP-1alpha over calvariae of normal mice evoked a striking increase in osteoclast formation, an effect dependent on RANK/RANKL signaling because MIP-1alpha had no effect in RANK-/- mice. Together, these results establish that MIP-1alpha is sufficient to induce MM-like destructive lesions in bone in vivo. Because, in the 5TGM1 model, blockade of osteoclastic resorption in other situations does not decrease tumor burden, we conclude that MIP-1alpha exerts a dual effect in myeloma, on osteoclasts, and tumor cells.

  • Source
    • "In preclinical mouse models, blocking of MIP-1α with antibody reduced severity of bone resorption. It seems that MIP-1α is a major player in MBD and its downregulation may help in controlling MBD.46 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Myeloma bone disease (MBD) is a devastating complication of multiple myeloma (MM). More than 80% of MM patients suffer from destructive bony lesions, leading to pain, fractures, mobility issues, and neurological deficits. MBD is not only a main cause of disability and morbidity in MM patients but also increases the cost of management. Bone destruction and lack of bone formation are main factors in the development of MBD. Some novel factors are found to be involved in the pathogenesis of MBD, eg, receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG) system (RANKL/OPG), Wingless (Wnt), dickkopf-1 (Wnt/DKK1) pathway. The addition of novel agents in the treatment of MM, use of bisphosphonates and other supportive modalities such as radiotherapy, vertebroplasty/kyphoplasty, and surgical interventions, all have significant roles in the treatment of MBD. This review provides an overview on the pathophysiology and management of MBD.
    Preview · Article · Aug 2014 · Cancer Growth and Metastasis
  • Source
    • "Animal protocols were approved by the Mayo Clinic Institutional Care and Use Committee. Female C57BL/KaLwRijHsd mice were obtained from Harlan Laboratories (Netherlands), and syngeneic murine myeloma 5TGM1 cells were implanted.33 For subcutaneous studies, 5×106 5TGM1 cells were implanted, and VSV (108 TCID50) was administered intravenously (IV; via the tail vein) 14 days later. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Vesicular stomatitis virus (VSV) is neuropathogenic in rodents but can be attenuated 50-fold by engineering the mouse interferon-beta (IFN-β) gene into its genome. Intravenously administered VSVs encoding IFN-β have potent activity against subcutaneous tumors in the 5TGM1 mouse myeloma model, without attendant neurotoxicity. However, when 5TGM1 tumor cells were seeded intravenously, virus-treated mice with advanced myeloma developed clinical signs suggestive of meningoencephalitis. Co-administration of a known active antimyeloma agent did not prolong survival, further suggesting that deaths were due to viral toxicity, not tumor burden. Histological analysis revealed that systemically administered 5TGM1 cells seed to the CNS, forming meningeal tumor deposits, and that VSV infects and destroys these tumors. Death is presumably a consequence of meningeal damage and/or direct transmission of virus to adjacent neural tissue. In light of these studies, extreme caution is warranted in clinical testing of attenuated VSVs, particularly in patients with CNS tumor deposits.Cancer Gene Therapy advance online publication, 1 November 2013; doi:10.1038/cgt.2013.63.
    Preview · Article · Nov 2013 · Cancer gene therapy
  • Source
    • "Bone marrow cells were flushed from the bone cavity of femurs and tibias of B6 mice (C57BL/6 J) with 2% heat-inactivated fetal bovine serum (Equitech-Bio, Kerrville, TX, USA) in PBS, and MSCs positive for CD73, CD90, CD105, CD146, CD166, Sca-1 and SSEA-4, but negative for CD11b, CD31, CD34 and CD45, were obtained as previously described [25]. The cells with MSC character were cultured with alpha minimum essential medium (Invitrogen) supplemented with 20% fetal bovine serum and 2 mM l-glutamine (Invitrogen) in a humidified atmosphere of 95% air and 5% CO2 at 37°C for 3 days before co-culture [26]. Additionally, MSCs, which had no Fas-L, were isolated from generalized lymphoproliferative disease (gld) mice for use in comparative experiments. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cell-based therapy represents a new frontier in the treatment of a wide variety of human diseases traditionally associated with morbidity outcomes, including those involving inflammation, autoimmunity, tissue damage, and cancer. However, the use of mesenchymal stem cells (MSCs) to treat multiple myeloma (MM) bone disease has raised concerns. Specifically, evidence has shown that infused MSCs might support tumor growth and metastasis. In this study, we used a standard disseminated MM model in mice to identify the in vivo effects of intravenous MSC infusion. In addition, a series of in vitro co-culture assays were preformed to explore whether Fas/Fas-L is involved in the inhibitory effects of MSCs on MM cells. In the MM mouse model, treatment of MSCs with highly expressed Fas ligand (FasLhigh MSCs) showed remarkable inhibitory effects on MM indenization in terms of extending the mouse survival rate and inhibiting tumor growth, bone resorption in the lumbus and collum femoris, and MM cell metastasis in the lungs and kidneys. In addition, reduced proliferation and increased apoptosis of MM cells was observed when co-cultured with FasLhigh MSCs in vitro. Furthermore, mechanistically, the binding between Fas and Fas Ligand (Fas-L) significantly induced apoptosis in MM cells, as evidenced through an increase in the expression of apoptosis marker and Fas in MM cells. In contrast, FasLnull MSCs promote MM growth. These data suggest that Fas-L/Fas-induced MM apoptosis plays a crucial role in the MSC-based inhibition of MM growth. Although whether MSCs inhibit or promote cancer growth remains controversial, the levels of FasL expression in MSCs determine, at least partially, the effects of MSCs on MM cell growth.
    Full-text · Article · Sep 2013 · Stem Cell Research & Therapy
Show more