Humoral Hypercalcemia of Malignancy (HHM) has been reported in association with a number of malignancies. In gynecologic malignancies, ovarian Clear Cell Carcinoma (CCC) is one of the most commonhistologic subtypes, w...Humoral Hypercalcemia of Malignancy (HHM) has been reported in association with a number of malignancies. In gynecologic malignancies, ovarian Clear Cell Carcinoma (CCC) is one of the most commonhistologic subtypes, whereas HHM caused by endometrial CCC is very rare. We report a case of endometrial CCC with HHM, with a low serum intact PTH level, elevated serum PTH-related Peptide (PTH-rP), and immunohistochemically demonstrated PTH-rP in the neoplasm.展开更多
Colorectal cancer(CRC)remains one of the leading causes of mortality from malignant diseases worldwide.In general terms,CRC presents high heterogeneity due to the influence of different genetic and environmental facto...Colorectal cancer(CRC)remains one of the leading causes of mortality from malignant diseases worldwide.In general terms,CRC presents high heterogeneity due to the influence of different genetic and environmental factors;also,the neoplastic cells are strongly influenced by the extracellular matrix and several surrounding cells,known together as the tumor microenvironment(TME).Bidirectional communication takes place between the tumor and the TME through the release of autocrine and paracrine factors.Parathyroid hormone-related peptide(PTHrP)is a cytokine secreted by a wide variety of tissues and is able to regulate several cellular functions both in physiological as well as in pathological processes.It exerts its effects as a paracrine/autocrine factor,although its mode of action is mainly paracrine.It has been shown that this peptide is expressed by several tumors and that the tumor secretion of PTHrP is responsible for the malignant humoral hypercalcemia.Eight years ago,when our research group started studying PTHrP effects in the experimental models derived from intestinal tumors,the literature available at the time addressing the effects of PTHrP on colorectal tumors was limited,and no articles had been published regarding to the paracrine action of PTHrP in CRC cells.Based on this and on our previous findings regarding the role of PTH in CRC cells,our purpose in recent years has been to explore the role of PTHrP in CRC.We analyzed the behavior of CRC cells treated with exogenous PTHrP,focalizing in the study of the following events:Survival,cell cycle progression and proliferation,migration,chemoresistance,tumor-associated angiogenesis,epithelial to mesenchymal transition program and other events also associated with invasion,such us the induction of cancer stem cells features.This work summarizes the major findings obtained by our investigation group using in vitro and in vivo CRC models that evidence the participation of PTHrP in the acquisition of an aggressive phenotype of CRC cells and the molecular mechanisms involved in these processes.Recently,we found that this cytokine induces this malignant behavior not only by its direct action on these intestinal cells but also through its influence on cells derived from TME,promoting a communication between CRC cells and surrounding cells that contributes to the molecular and morphological changes observed in CRC cells.These investigations establish the basis for our next studies in order to address the clinical applicability of our findings.Recognizing the factors and mechanisms that promote invasion in CRC cells,evasion to the cytotoxic effects of current CRC therapies and thus metastasis is decisive for the identification of new markers with the potential to improve early diagnosis and/or to predict prognosis,to predetermine drug resistance and to provide treatment guidelines that include targeted therapies for this disease.展开更多
IgG Heavy Chain Disease (γHCD) is a rare plasma cell disorder. Hypercalcemia related to plasma cell dyscrasias is related to non-PTHrP related mechanisms. Here we describe the first case of a patient with γHCD and P...IgG Heavy Chain Disease (γHCD) is a rare plasma cell disorder. Hypercalcemia related to plasma cell dyscrasias is related to non-PTHrP related mechanisms. Here we describe the first case of a patient with γHCD and PTHrP related hypercalcemia. Methods: Patient case derived from chart review from 2011 to 2015. Literature review performed searching PubMed 1968-current. Results: The patient was diagnosed with hypercalcemia with elevated PTHrP and exclusion of other etiologies of hypercalcemia. She was diagnosed with (γHCD) by M-spike 0.64 g/dL, IFE showing a broad band of IgG heavy chain, without associated light chains and severe depression of the non-mono-clonal IgG. Serum immunoglobulins demonstrated elevated IgG (2110 mg/dL), normal IgA (46 mg/dL) and decreased IgM (<21 mg/dL). Bone marrow biopsy showed 5% PCs, non-clonal by kappa/lambda, but exclusive for IgG by IHC, without any staining for IgA or IgM. The patient was started on therapy with improved hypercalcemia and PTHrP levels. Conclusions: This is the first reported case of γHCD presenting with PTHrP related hypercalcemia. Given that skeletal involvement is uncommon in γHCD, hypercalcemia secondary to γHCD may at times be a PTHrP driven phenomenon and we recommend that this test be ordered in such cases.展开更多
目的探讨人甲状旁腺激素相关蛋白1-34片段(human parathyroid hormone related protein,PTHrP1-34)对去卵巢骨质疏松大鼠的作用。方法60只4月龄Wistar健康雌性大鼠,40只行双侧卵巢摘除术,20只做假手术,6周后各处死10只证实骨质疏松造模...目的探讨人甲状旁腺激素相关蛋白1-34片段(human parathyroid hormone related protein,PTHrP1-34)对去卵巢骨质疏松大鼠的作用。方法60只4月龄Wistar健康雌性大鼠,40只行双侧卵巢摘除术,20只做假手术,6周后各处死10只证实骨质疏松造模成功。余30只骨质疏松模型鼠随机分为PTHrP治疗组、雌二醇治疗组(E2组)和安慰剂组(Placebo组),10只假手术组作对照。治疗3个月后,测定并比较股骨、股椎骨密度(BMD)、血清钙、磷、感性磷酸酶(ALP)、雌激素(E2)、肿瘤坏死因子-α(TNF-α)、骨钙素(BGP)、胰岛素样生长因了(IGF-1)水平。结果治疗后,PTHrP股有和腰椎BMD较Placebo组明显升高;血清BGP及IGF-1水平也明显高于Placebo组;PTHrP治疗组血清TNF-α无明显变化。结论hPTHrP1-34能通过刺激成骨细胞的活性,增加骨密度,对去卵巢大鼠所引起的骨质疏松有效。展开更多
目的探讨间歇性甲状旁腺激素相关蛋白(parathyroid hormone related protein,PTHrP)刺激在成牙骨质细胞中对细胞凋亡和成牙骨质矿化相关蛋白和细胞因子表达的影响。方法应用成牙骨质细胞OCCM-30,使用PTHrP(1-36)、甲状旁腺激素I型受体(p...目的探讨间歇性甲状旁腺激素相关蛋白(parathyroid hormone related protein,PTHrP)刺激在成牙骨质细胞中对细胞凋亡和成牙骨质矿化相关蛋白和细胞因子表达的影响。方法应用成牙骨质细胞OCCM-30,使用PTHrP(1-36)、甲状旁腺激素I型受体(parathyroid hormone type I receptor,PTH1R)阻断剂PTHrP(7-34)对细胞进行间歇性刺激,间歇性给药模式包含3个周期,48 h/周期,分为对照组、PTHrP(1-36)组及PTH1R阻断剂组。采用流式细胞术检测细胞凋亡;采用茜素红染色观察矿化功能;采用real-time PCR和Western blotting法检测细胞内成牙骨质矿化相关蛋白-骨桥素(osteopontin,OPN)、I型胶原蛋白(collagen-1,COL-1)及成牙骨质相关细胞因子I型胰岛素样生长因子-1(insulin like growth factor-1,IGF-1)的基因表达及蛋白质表达。结果间断性PTHrP抑制成牙骨质细胞凋亡,PTH1R阻断剂促进成牙骨质细胞凋亡(P<0.05);PTHrP间断性刺激能够显著增加成牙骨质细胞内OPN、COL-1、IGF-1基因及蛋白表达(P<0.05);PTH1R阻断剂抑制成牙骨质细胞内OPN、COL-1、IGF-1基因及蛋白表达(P<0.05)。结论间断性PTHrP可通过与成牙骨质细胞上PTH1R相互作用抑制细胞凋亡,促进成牙骨质细胞矿化以及相关蛋白和细胞因子的表达。展开更多
Aim:Estrogen receptorα-positive(ER+)subtypes of breast cancer have the greatest predilection for forming osteolytic bone metastases(BMETs).Because tumor-derived factors mediate osteolysis,a possible role for tumoral...Aim:Estrogen receptorα-positive(ER+)subtypes of breast cancer have the greatest predilection for forming osteolytic bone metastases(BMETs).Because tumor-derived factors mediate osteolysis,a possible role for tumoral ERαsignaling in driving ER+BMET osteolysis was queried using an estrogen(E2)-dependent ER+breast cancer BMET model.Methods:Female athymic Foxn1nu mice were inoculated with human ER+MCF-7 breast cancer cells via the left cardiac ventricle post-E2 pellet placement,and age-and dose-dependent E2 effects on osteolytic ER+BMET progression,as well as direct bone effects of E2,were determined.Results:Osteolytic BMETs,which did not form in the absence of E2 supplementation,occurred with the same frequency in young(5-week-old)vs.skeletally mature(16-week-old)E2(0.72 mg)-treated mice,but were larger in young mice where anabolic bone effects of E2 were greater.However,in mice of a single age and across a range of E2 doses,anabolic E2 bone effects were constant,while osteolytic ER+BMET lesion incidence and size increased in an E2 dose-dependent fashion.Osteoclasts in ER+tumor-bearing(but not tumor-naive)mice increased in an E2-dose dependent fashion at the bone-tumor interface,while histologic tumor size and proliferation did not vary with E2 dose.E2-inducible tumoral secretion of the osteolytic factor parathyroid hormone-related protein(PTHrP)was dose-dependent and mediated by ERα,with significantly greater levels of secretion from ER+BMET-derived tumor cells.Conclusion:These results suggest that tumoral ERαsignaling may contribute to ER+BMET-associated osteolysis,potentially explaining the greater predilection for ER+tumors to form clinically-evident osteolytic BMETs.展开更多
文摘Humoral Hypercalcemia of Malignancy (HHM) has been reported in association with a number of malignancies. In gynecologic malignancies, ovarian Clear Cell Carcinoma (CCC) is one of the most commonhistologic subtypes, whereas HHM caused by endometrial CCC is very rare. We report a case of endometrial CCC with HHM, with a low serum intact PTH level, elevated serum PTH-related Peptide (PTH-rP), and immunohistochemically demonstrated PTH-rP in the neoplasm.
基金Supported by Agencia Nacional de Promoción Científica y Tecnológica,No. PICT-2013-1441Consejo Nacional de Investigaciones Científicas y Técnicas,No. PIP11220150100350+3 种基金Instituto Nacional del Cáncer,Asistencia financiera Ⅱ,No. 12002-4395-14-1Instituto Nacional del Cáncer,Asistencia Financiera Ⅲ,No. RESOL-2016-1006-E-APN-MSUniversidad Nacional del Sur,Argentina,No. PGI:24/B230PGI:24/B303
文摘Colorectal cancer(CRC)remains one of the leading causes of mortality from malignant diseases worldwide.In general terms,CRC presents high heterogeneity due to the influence of different genetic and environmental factors;also,the neoplastic cells are strongly influenced by the extracellular matrix and several surrounding cells,known together as the tumor microenvironment(TME).Bidirectional communication takes place between the tumor and the TME through the release of autocrine and paracrine factors.Parathyroid hormone-related peptide(PTHrP)is a cytokine secreted by a wide variety of tissues and is able to regulate several cellular functions both in physiological as well as in pathological processes.It exerts its effects as a paracrine/autocrine factor,although its mode of action is mainly paracrine.It has been shown that this peptide is expressed by several tumors and that the tumor secretion of PTHrP is responsible for the malignant humoral hypercalcemia.Eight years ago,when our research group started studying PTHrP effects in the experimental models derived from intestinal tumors,the literature available at the time addressing the effects of PTHrP on colorectal tumors was limited,and no articles had been published regarding to the paracrine action of PTHrP in CRC cells.Based on this and on our previous findings regarding the role of PTH in CRC cells,our purpose in recent years has been to explore the role of PTHrP in CRC.We analyzed the behavior of CRC cells treated with exogenous PTHrP,focalizing in the study of the following events:Survival,cell cycle progression and proliferation,migration,chemoresistance,tumor-associated angiogenesis,epithelial to mesenchymal transition program and other events also associated with invasion,such us the induction of cancer stem cells features.This work summarizes the major findings obtained by our investigation group using in vitro and in vivo CRC models that evidence the participation of PTHrP in the acquisition of an aggressive phenotype of CRC cells and the molecular mechanisms involved in these processes.Recently,we found that this cytokine induces this malignant behavior not only by its direct action on these intestinal cells but also through its influence on cells derived from TME,promoting a communication between CRC cells and surrounding cells that contributes to the molecular and morphological changes observed in CRC cells.These investigations establish the basis for our next studies in order to address the clinical applicability of our findings.Recognizing the factors and mechanisms that promote invasion in CRC cells,evasion to the cytotoxic effects of current CRC therapies and thus metastasis is decisive for the identification of new markers with the potential to improve early diagnosis and/or to predict prognosis,to predetermine drug resistance and to provide treatment guidelines that include targeted therapies for this disease.
文摘IgG Heavy Chain Disease (γHCD) is a rare plasma cell disorder. Hypercalcemia related to plasma cell dyscrasias is related to non-PTHrP related mechanisms. Here we describe the first case of a patient with γHCD and PTHrP related hypercalcemia. Methods: Patient case derived from chart review from 2011 to 2015. Literature review performed searching PubMed 1968-current. Results: The patient was diagnosed with hypercalcemia with elevated PTHrP and exclusion of other etiologies of hypercalcemia. She was diagnosed with (γHCD) by M-spike 0.64 g/dL, IFE showing a broad band of IgG heavy chain, without associated light chains and severe depression of the non-mono-clonal IgG. Serum immunoglobulins demonstrated elevated IgG (2110 mg/dL), normal IgA (46 mg/dL) and decreased IgM (<21 mg/dL). Bone marrow biopsy showed 5% PCs, non-clonal by kappa/lambda, but exclusive for IgG by IHC, without any staining for IgA or IgM. The patient was started on therapy with improved hypercalcemia and PTHrP levels. Conclusions: This is the first reported case of γHCD presenting with PTHrP related hypercalcemia. Given that skeletal involvement is uncommon in γHCD, hypercalcemia secondary to γHCD may at times be a PTHrP driven phenomenon and we recommend that this test be ordered in such cases.
文摘目的探讨人甲状旁腺激素相关蛋白1-34片段(human parathyroid hormone related protein,PTHrP1-34)对去卵巢骨质疏松大鼠的作用。方法60只4月龄Wistar健康雌性大鼠,40只行双侧卵巢摘除术,20只做假手术,6周后各处死10只证实骨质疏松造模成功。余30只骨质疏松模型鼠随机分为PTHrP治疗组、雌二醇治疗组(E2组)和安慰剂组(Placebo组),10只假手术组作对照。治疗3个月后,测定并比较股骨、股椎骨密度(BMD)、血清钙、磷、感性磷酸酶(ALP)、雌激素(E2)、肿瘤坏死因子-α(TNF-α)、骨钙素(BGP)、胰岛素样生长因了(IGF-1)水平。结果治疗后,PTHrP股有和腰椎BMD较Placebo组明显升高;血清BGP及IGF-1水平也明显高于Placebo组;PTHrP治疗组血清TNF-α无明显变化。结论hPTHrP1-34能通过刺激成骨细胞的活性,增加骨密度,对去卵巢大鼠所引起的骨质疏松有效。
文摘目的探讨间歇性甲状旁腺激素相关蛋白(parathyroid hormone related protein,PTHrP)刺激在成牙骨质细胞中对细胞凋亡和成牙骨质矿化相关蛋白和细胞因子表达的影响。方法应用成牙骨质细胞OCCM-30,使用PTHrP(1-36)、甲状旁腺激素I型受体(parathyroid hormone type I receptor,PTH1R)阻断剂PTHrP(7-34)对细胞进行间歇性刺激,间歇性给药模式包含3个周期,48 h/周期,分为对照组、PTHrP(1-36)组及PTH1R阻断剂组。采用流式细胞术检测细胞凋亡;采用茜素红染色观察矿化功能;采用real-time PCR和Western blotting法检测细胞内成牙骨质矿化相关蛋白-骨桥素(osteopontin,OPN)、I型胶原蛋白(collagen-1,COL-1)及成牙骨质相关细胞因子I型胰岛素样生长因子-1(insulin like growth factor-1,IGF-1)的基因表达及蛋白质表达。结果间断性PTHrP抑制成牙骨质细胞凋亡,PTH1R阻断剂促进成牙骨质细胞凋亡(P<0.05);PTHrP间断性刺激能够显著增加成牙骨质细胞内OPN、COL-1、IGF-1基因及蛋白表达(P<0.05);PTH1R阻断剂抑制成牙骨质细胞内OPN、COL-1、IGF-1基因及蛋白表达(P<0.05)。结论间断性PTHrP可通过与成牙骨质细胞上PTH1R相互作用抑制细胞凋亡,促进成牙骨质细胞矿化以及相关蛋白和细胞因子的表达。
基金supported by the National Cancer Institute(NCI)of the National Institutes of Health(NIH)(R03CA181893 and R01CA174926 to JLF,T32CA00923,P30CA023074)METAvivor(Translational Research Award,JLF)+1 种基金the Phoenix Chapter of ARCS Foundation(JNC)and the Louise Foucar Marshall Foundation Dissertation Fellowship(JNC).
文摘Aim:Estrogen receptorα-positive(ER+)subtypes of breast cancer have the greatest predilection for forming osteolytic bone metastases(BMETs).Because tumor-derived factors mediate osteolysis,a possible role for tumoral ERαsignaling in driving ER+BMET osteolysis was queried using an estrogen(E2)-dependent ER+breast cancer BMET model.Methods:Female athymic Foxn1nu mice were inoculated with human ER+MCF-7 breast cancer cells via the left cardiac ventricle post-E2 pellet placement,and age-and dose-dependent E2 effects on osteolytic ER+BMET progression,as well as direct bone effects of E2,were determined.Results:Osteolytic BMETs,which did not form in the absence of E2 supplementation,occurred with the same frequency in young(5-week-old)vs.skeletally mature(16-week-old)E2(0.72 mg)-treated mice,but were larger in young mice where anabolic bone effects of E2 were greater.However,in mice of a single age and across a range of E2 doses,anabolic E2 bone effects were constant,while osteolytic ER+BMET lesion incidence and size increased in an E2 dose-dependent fashion.Osteoclasts in ER+tumor-bearing(but not tumor-naive)mice increased in an E2-dose dependent fashion at the bone-tumor interface,while histologic tumor size and proliferation did not vary with E2 dose.E2-inducible tumoral secretion of the osteolytic factor parathyroid hormone-related protein(PTHrP)was dose-dependent and mediated by ERα,with significantly greater levels of secretion from ER+BMET-derived tumor cells.Conclusion:These results suggest that tumoral ERαsignaling may contribute to ER+BMET-associated osteolysis,potentially explaining the greater predilection for ER+tumors to form clinically-evident osteolytic BMETs.
