Constitutive production of parathyroid hormone-related protein (PTHrP) by fibroblasts derived from normal and pathological human breast tissue.
Constitutive production of parathyroid hormone-related protein (PTHrP) by fibroblasts derived from normal and pathological human breast tissue.
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发表时间：
2002
影响因子：
3.1
通讯作者：
M. Cros;C. Cataisson;Y. Cho;Y. Berthois;O. Bernard-Poenaru;M. Denne;A. Graulet;M. de Vernejoul;J. Foley;Z. Bouizar
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作者：
M. Cros;C. Cataisson;Y. Cho;Y. Berthois;O. Bernard-Poenaru;M. Denne;A. Graulet;M. de Vernejoul;J. Foley;Z. Bouizar
甲状旁腺激素相关蛋白（PTHrP）在乳腺中表达，似乎对该结构的形态发生至关重要。乳腺中PTHrP的产生通常归因于上皮细胞。由于乳腺的基质成分产生与乳腺上皮组织和肿瘤的增殖和分化有关的因子，本研究的目的是研究乳腺癌肿瘤和正常乳腺的乳腺成纤维细胞PTHrP的表达。PTHrP抗体标记正常乳腺小叶内成纤维细胞和肿瘤细胞周围的基质成纤维细胞。PTHrP是由培养的乳腺成纤维细胞组成性产生的，不依赖于血清刺激。正常（15.83 +/- 1.72 fmol/10（6）细胞）和病理性乳腺成纤维细胞（19.87 +/- 5.76）分泌相似量的PTHrP。RT-PCR法检测所有受检标本中PTH/PTHrP受体mRNA的表达。正常乳腺的成纤维细胞对PTH和PTHrP-cAMP都有反应（分别为453 +/- 133%和513 +/-133%，来自基础刺激），而病理性乳腺成纤维细胞对PTHrP-cAMP反应最低（183 +/- 36%）。还检测了与肿瘤生长和侵袭性有关的其他成纤维细胞因子的产生。白细胞介素-6（IL-6）、肿瘤坏死因子-α（INF-α）和基质金属蛋白酶原（MMP）-1不受组织状态的影响。相比之下，与来自正常供体的成纤维细胞（125 +/- 41 ng/10（6）个细胞）相比，来自病理性样本（290 +/- 62 ng/10（6）个细胞）的成纤维细胞中产生的pro-MMP-2水平增加。PTHrP的产生与TNF-α和pro-MMP-2的产生相关。然而，抑制特异性中和抗体对TNF-α或PTHrP，或与PTHrP拮抗剂，表明这些因素并不相互调节。总之，乳腺成纤维细胞是组成型PTHrP产生细胞，具有通过PTH/PTHrP受体进行自分泌信号传导的潜力。
Parathyroid hormone-related protein (PTHrP) is expressed in the mammary gland and appears to be critical to the morphogenesis of this structure. PTHrP production in the breast is generally attributed to epithelial cells. Because the stromal component of the breast produces factors implicated in proliferation and differentiation of mammary epithelial tissue and tumors, the aim of this study was to investigate the PTHrP expression by mammary fibroblasts from breast cancer tumors and normal breast. PTHrP antibodies labeled intralobular fibroblasts in normal breast and stromal fibroblasts that surround tumor cells. PTHrP was constitutively produced by the cultured mammary fibroblasts, independent of serum stimulation. Normal (15.83 +/- 1.72 fmol/10(6) cells) and pathological breast fibroblasts (19.87 +/- 5.76) secreted similar amounts of PTHrP. PTH/PTHrP receptor mRNA was detected by RT-PCR in all the samples tested. Fibroblasts from normal breast were both PTH and PTHrP-cAMP responsive (453 +/- 133% and 513 +/- 133%, respectively, from basal stimulation), whereas pathological breast fibroblasts were minimally PTHrP-cAMP responsive (183 +/- 36%). The production of other fibroblastic factors implicated in tumor growth and invasiveness was also examined. Interleukin-6 (IL-6), tumor necrosis factor-alpha (INF-alpha), and pro-matrix metalloproteinase (MMP)-1 were not affected by the status of the tissue. In contrast, increased levels of pro-MMP-2 were produced in fibroblasts that originated from pathological (290 +/- 62 ng/10(6) cells) samples compared with those from normal donors (125 +/- 41 ng/10(6) cells). PTHrP production was correlated with TNF-alpha and pro-MMP-2 production. However, inhibition with specific neutralizing antibodies against TNF-alpha or PTHrP, or with a PTHrP antagonist, showed that these factors did not regulate each other. In conclusion, breast fibroblasts are constitutive PTHrP-producing cells with the potential for autocrine signaling through the PTH/PTHrP receptor.