Hypercalcemia, Parathyroid Hormone-Related Protein Expression and Human T-cell Leukemia Virus Infection

Prager, Denis J.; Rosenblatt, J. D.; Ejima, Eri

doi:10.3109/10428199409049695

Cited by 36 publications

(29 citation statements)

References 42 publications

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“…With an unusually high association of hypercalcemia, about 40% of patients with ATL are known to eventually develop hypercalcemia (15,16). On the other hand, breast carcinoma was relatively uncommon in our series as well as in other Asian studies (9,10), in contrast to Western series with this carcinoma typically accounting for more than 20% (3,6,(17)(18)(19).…”

Section: The Major Causes Of Hypercalcemia Were Found To Be Malignanccontrasting

confidence: 48%

The Causes of Hypercalcemia in Okinawan Patients: AnInternational Comparison

2007

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Section: The Major Causes Of Hypercalcemia Were Found To Be Malignanccontrasting

confidence: 48%

The Causes of Hypercalcemia in Okinawan Patients: AnInternational Comparison

2007

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“…During the multi-stage carcinogenesis of ATLL, T-cell transformation, proliferation and progression require the effects of humoral and local factors. In previous studies, we and others have shown that both PTHrP and MIP-1α are important for HHM development in ATLL [3,4,7,8,48,49]. Interestingly, we also found that both factors were expressed in the early stages of ex vivo T-cell transformation and immortalization [13].…”

Section: Discussionsupporting

confidence: 53%

Effects of parathyroid hormone-related protein and macrophage inflammatory protein-1α in Jurkat T-cells on tumor formationin vivoand expression of apoptosis regulatory genesin vitro

Shu

Dirksen²,

Lanigan³

et al. 2012

Leukemia & Lymphoma

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Parathyroid hormone-related protein (PTHrP) and macrophage inflammatory protein-1α (MIP-1α) have been implicated in the pathogenesis of adult T-cell leukemia/lymphoma, but their effects on T-cells have not been well studied. Here we analyzed the functions of PTHrP and MIP-1α on T-cell growth and death both in vitro and in vivo by overexpressing either factor in human Jurkat T-cells. PTHrP or MIP-1α did not affect Jurkat cell growth in vitro, but PTHrP increased their sensitivity to apoptosis. Importantly, PTHrP and MIP-1α decreased both tumor incidence and growth in vivo. To investigate possible mechanisms, polymerase chain reaction (PCR) arrays and real-time reverse transcription (RT)-PCR assays were performed. Both PTHrP and MIP-1α increased the expression of several factors including signal transducer and activator of transcription 4, tumor necrosis factor α, receptor activator of nuclear factor κB ligand and death-associated protein kinase 1, and decreased the expression of inhibitor of DNA binding 1, interferon γ and CD40 ligand in Jurkat cells. In addition, MIP-1α also increased the expression of transcription factor AP-2α and PTHrP increased expression of the vitamin D3 receptor. These data demonstrate that PTHrP and MIP-1α exert a profound antitumor effect presumably by increasing the sensitivity to apoptotic signals through modulation of transcription and apoptosis factors in T-cells.

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“…1). Eighty percent of ATLL patients develop humoral hypercalcemia of malignancy (HHM), a severe complication resulting from increased osteoclastic bone resorption and renal calcium reabsorption (2). HHM in ATLL patients leads to a mean survival of <1 year (3); therefore, it is urgent to develop new therapies to sufficiently reduce HHM and eliminate tumor progression in ATLL.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, PTHrP plays a major role in the pathogenesis of HHM (10); however, recent studies have suggested that cytokines and chemokines, such as MIP-1a, a chemoattractant and activator of monocytes during inflammation, can induce osteoclastic bone resorption and serve as a potential survival and osteoclast stimulatory factor in cancer (11). Increased concentrations of plasma PTHrP and MIP-1a are reliable clinical biomarkers of hypercalcemia in ATLL and represent potential therapeutic targets (2,9).…”

Section: Introductionmentioning

confidence: 99%

A Novel Bioluminescent Mouse Model and Effective Therapy for Adult T-Cell Leukemia/Lymphoma

Shu¹,

Nadella²,

Dirksen³

et al. 2007

Cancer Research

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Adult T-cell /lymphomaleukemia (ATLL) is caused by human T-cell lymphotropic virus type 1 (HTLV-1). Approximately 80% of ATLL patients develop humoral hypercalcemia of malignancy (HHM), a life-threatening complication leading to a poor prognosis. Parathyroid hormone-related protein (PTHrP) and macrophage inflammatory protein-1A (MIP-1A) are important factors in the pathogenesis of HHM in ATLL and the expression of PTHrP can be activated by nuclear factor KB (NF-KB). NF-KB is constitutively activated in ATLL cells and is essential for leukemogenesis including transformation of lymphocytes infected by HTLV-1. Our goal was to evaluate the effects of NF-KB disruption by a proteasomal inhibitor (PS-341) and osteoclastic inhibition by zoledronic acid (Zol) on the development of ATLL and HHM using a novel bioluminescent mouse model. We found that PS-341 decreased cell viability, increased apoptosis, and down-regulated PTHrP expression in ATLL cells in vitro. To investigate the in vivo efficacy, nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice were xenografted with ATLL cells and treated with vehicle control, PS-341, Zol, or a combination of PS-341 and Zol. Bioluminescent imaging and tumor cell count showed a significant reduction in tumor burden in mice from all treatment groups. All treatments also significantly reduced the plasma calcium concentrations. Zol treatment increased trabecular bone volume and decreased osteoclast parameters. PS-341 reduced PTHrP and MIP-1A expression in tumor cells in vivo. Our results indicate that both PS-341 and Zol are effective treatments for ATLL and HHM, which are refractory to conventional therapy. [Cancer Res 2007;67(24):11859-66]

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Hypercalcemia, Parathyroid Hormone-Related Protein Expression and Human T-cell Leukemia Virus Infection

Cited by 36 publications

References 42 publications

The Causes of Hypercalcemia in Okinawan Patients: AnInternational Comparison

The Causes of Hypercalcemia in Okinawan Patients: AnInternational Comparison

Effects of parathyroid hormone-related protein and macrophage inflammatory protein-1α in Jurkat T-cells on tumor formationin vivoand expression of apoptosis regulatory genesin vitro

A Novel Bioluminescent Mouse Model and Effective Therapy for Adult T-Cell Leukemia/Lymphoma

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