A Destructive Cascade Mediated by CCL2 Facilitates Prostate Cancer Growth in Bone

Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, Michigan MI 48109-1078, USA.
Cancer Research (Impact Factor: 9.33). 02/2009; 69(4):1685-92. DOI: 10.1158/0008-5472.CAN-08-2164
Source: PubMed


Monocyte chemoattractant protein 1 (CCL2) is a recently identified prominent regulator of prostate cancer growth and metastasis. The purpose of this study was to investigate the mechanistic role of CCL2 in prostate cancer growth in bone. The present study found that CCL2 was up-regulated in osteoblasts (3-fold by PC-3 and 2-fold by VCaP conditioned medium) and endothelial cells (2-fold by PC-3 and VCaP conditioned medium). Parathyroid hormone-related protein (PTHrP) treatment of osteoblastic cells up-regulated CCL2 and was blocked by a PTHrP antagonist, suggesting that prostate cancer-derived PTHrP plays an important role in elevation of osteoblast-derived CCL2. CCL2 indirectly increased blood vessel formation in endothelial cells through vascular endothelial growth factor-A, which was up-regulated 2-fold with administration of CCL2 in prostate cancer cells. In vivo, anti-CCL2 treatment suppressed tumor growth in bone. The decreased tumor burden was associated with decreased bone resorption (serum TRAP5b levels were decreased by 50-60% in anti-CCL2-treated animals from VCaP or PC-3 cell osseous lesions) and microvessel density was decreased by 70% in anti-CCL2-treated animals with bone lesions from VCaP cells. These data suggest that a destructive cascade is driven by tumor cell-derived, PTHrP-mediated induction of CCL2, which facilitates tumor growth via enhanced osteoclastic and endothelial cell activity in bone marrow. Taken together, CCL2 mediates the interaction between tumor-derived factors and host-derived chemokines acting in cooperation to promote skeletal metastasis.

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Available from: Linda A Snyder, Mar 02, 2015
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    • "Multiple studies demonstrate that PTHrP plays a major role in tumors that metastasize to the bone, such as breast and prostate cancer [13] [14] [15]. There is now increasing evidence that PTHrP also plays a role in cancers that metastasize to other regions of the body [16] [17] [18] [19] [20], such as colon tumors which show a preference for liver metastasis [2]. Apoptosis is especially relevant in the gastrointestinal tract, as this tissue undergoes a continued process of cell turnover that is essential for its normal function [21]. "
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    ABSTRACT: We have previously demonstrated that parathyroid hormone (PTH) induces apoptosis in human colon adenocarcinoma Caco-2 cells but the effects of its tumoral analog PTH-related peptide (PTHrP) in this cell line are still unknown. In the present work we investigated whether PTHrP, as PTH, is able to induce Caco-2 cells apoptosis or if it exerts protective effects under apoptotic conditions. Using Caco-2 cells cultured under serum deprivation in the presence or absence of PTHrP we demonstrated that, differently to PTH, its analog employed at the same concentration (10(-8)M) is not a pro-apoptotic hormone. Cells were exposed to an oxidative insult in the form of hydrogen peroxide to induce apoptosis, which leads to 50%-loss of cell viability determined by MTS assay, morphological changes observed under fluorescence microscopy and Western blot analysis. Herein we demonstrate, for the first time, that the pre-treatment with PTHrP prior to H2O2 incubation, prevents the cell death induced by the apoptotic inductor; and using specific inhibitors we evidenced that AKT, ERK1/2, JNK1/2 and p38 MAPK mediate this anti-apoptotic effect. Also, we found that PTHrP decreases the pro-apoptotic protein BAX levels and increases the protein expression of the anti-apoptotic HSP27. Immunoblot analysis revealed that H2O2 increases the phosphorylation levels of AKT and MAPKs, exhibiting a cellular defense response; and consequently increases phospho-BAD levels. The H2O2-induced activation of protein kinases is reverted when cells are pre-treated with PTHrP. Altogether these results evidence a protective effect of PTHrP under apoptotic conditions in intestinal cells, which may be mediated by AKT and MAPKs.
    Biochimica et Biophysica Acta 07/2013; 1833(12). DOI:10.1016/j.bbamcr.2013.06.029 · 4.66 Impact Factor
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    • "Expression of CCL2 recruits tumor-associated macrophages, which is responsible for the prometastatic effect in the ER-negative breast cancers [6]. Moreover, CCL2 directly interacts with CCR2 on the endothelial cell surface, leading to increased vessel sprout formation and angiogenesis [7] [8]. It has been shown that polymorphisms of CCL2 and CCR2-64I are associated with transitional bladder cell carcinoma [9] [10]. "
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    • "The identification of several homing factors [3] [5] [6], host and tumorderived factors that are essential for tumor growth in bone [7] [8], has been achieved. Hematopoietic stem cells (HSCs) " home " to the bone marrow, as do PCa cells, and compete for occupancy of the HSC niche [9]. "
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