Mechanism of malignant hypercalcaemia in carcinoma of the breast.

To investigate the mechanisms of hypercalcaemia in carcinoma of the breast, 22 patients with hypercalcaemia due to metastatic carcinoma were studied and the findings compared with those obtained in normal subjects and patients with benign and malignant breast disease without hypercalcaemia. As expected, patients with metastases of bone showed biochemical evidence of increased bone resorption. Whereas all patients with hypercalcaemia had skeletal metastases, not all patients with skeletal metastases had hypercalcaemia despite considerable degrees of bone resorption. The presence of hypercalcaemia was associated with a significant increase in renal tubular reabsorption of calcium (p less than 0.001) and decreased reabsorption of phosphate (p less than 0.001) despite adequate rehydration of patients. These studies suggest that increased renal tubular reabsorption of calcium, possibly mediated by a humoral factor with activity similar to that of parathyroid hormone, contributes appreciably to the hypercalcaemia of malignant breast disease.     

Bone resorption and circulating PTH-like bioactivity in an animal model of hypercalcaemia of malignancy

An in vivo model of humoral hypercalcaemia of malignancy has been used to examine the role of circulating PTH-like bioactivity in the development of bone resorption and hypercalcaemia. After inoculation of cells from a renal carcinoma cell line into nude mice, circulating PTH-like bioactivity as measured by the sensitive renal and metatarsal cytochemical bioassays for PTH was elevated in only 18% and 53% of the mice respectively. Bone resorption was elevated in all the mice investigated irrespective of the level of PTH-like bioactivity. Thus, in this model, while the circulating PTH-like moiety is more potent when acting on bone, it did not correlate with the degree of bone resorption suggesting that it may not be the sole cause of the hypercalcaemia.     

Endocrine and Metabolic Disorders in Bronchial Carcinoma

In an unselected series of 185 patients with histologically confirmed bronchial carcinoma 16 had endocrine disturbances attributable to the tumour (excluding pulmonary osteoarthropathy). Of these, 11 patients had hypercalcaemia; three inappropriate secretion of antidiuretic hormone; one Cushing''s disease; three hypertrophic osteoarthropathy; and one gynaecomastia. Cushing''s disease and inappropriate antidiuresis are specifically associated with oat-cell tumours, and hypercalcaemia occurs most frequently with squamous carcinoma. A negative correlation exists between gynaecomastia and osteoarthropathy on the one hand and oat-cell carcinoma on the other.     

HMGB1在卵巢癌中的表达及临床意义

目的：探讨高迁移率组蛋白B1（HMGB1）在卵巢癌患者血清及组织中的表达及临床意义。方法：采用ELISA技术检测96例女性血清中HMGB1水平,其中盆腔肿物住院患者66例按照术后病理结果分为卵巢良性肿瘤组40例和卵巢癌组26例,健康女性30例作为正常对照组,并通过免疫组织化学技术进一步检测卵巢癌、卵巢良性肿瘤组织中的表达情况。结果：卵巢癌组HMGB1水平明显高于其他两组,差异有统计学意义（P〈0.05）,正常对照组和卵巢良性肿瘤组比较差异无统计学意义（P〉0.05）。结论：HMGB1测定有助于鉴别卵巢良恶性肿瘤。     

Expression of CD40 and growth-inhibitory activity of CD40 agonist in ovarian carcinoma cells

The CD40 receptor is a member of the tumour necrosis factor receptor family and is widely expressed on various cell types. The antitumour activity of CD40 agonist antibody has been observed in B-cell-derived malignancies, but its activity on ovarian cancer remains unclear. However, in this paper, we first confirmed that the anti-CD40 agonist antibody could inhibit the growth of ovarian cancer cells and induce apoptosis. This study investigated the expression of CD40 by ovarian carcinoma tissues and cell lines, at the same time, we evaluated the effect of a recombinant soluble human CD40L (rshCD40L) and an anti-CD40 agonist antibody on cell growth and apoptosis. Flow cytometry and immunohistochemistry assay demonstrated that CD40 was expressed on ovarian carcinoma cell lines and primary ovarian carcinoma cells derived from ascites, as well as on ovarian carcinoma tissues. The growth inhibition of rshCD40L and the anti-CD40 agonist antibody on ovarian carcinoma cells was examined by MTT assay, and the proportion of apoptotic tumour cells was analysed by flow cytometry and Hoechst staining. Our study showed that CD40 was expressed on all ovarian carcinoma cell lines and was examined in 86.2% (162/188) of ovarian cancer tissue samples, but not in normal ovarian tissues (n?=?20). Treatment with rshCD40L or anti-CD40 agonist antibody significantly inhibited ovarian carcinoma cell growth and induced apoptosis. Theses results suggest that CD40 is expressed on ovarian carcinoma cells, moreover, that rshCD40L and anti-CD40 agonist antibody have therapeutic potential to inhibit human ovarian cancer growth.     

FLIP、FADD在上皮性卵巢癌中表达及其临床意义

目的：研究FLIP、FADD在上皮性卵巢癌组织中的表达情况,探讨二者在上皮性卵巢癌发生发展中的作用及其临床意义。方法：采用免疫组化SP法及RT—PCR法检测44例上皮性卵巢癌及17例正常卵巢组织中FLIP、FADD的表达,并检测上皮性卵巢癌中PCNA的表达,分析FLIP,FADD表达与上皮性卵巢癌临床病理参数及PCNA表达的关系。结果：FLIP、FADD在上皮性卵巢癌组织中的阳性表达率,与正常卵巢组织相比,差异有统计学意义（P〈0．05）。FLIP,FADD表达与上皮性卵巢癌病理分级及临床分期有关,FLIP、FADD在I—II期中的阳性表达率,与III．IV期相比,差异有统计学意义（P〈0．05）。FLIP、FADD在病理组织学-1级中的阳性表达率,与2—3级相比,差异有统计学意义（P〈0．05）。FLIP、FADD的表达与患者年龄、组织学分型及淋巴结转移无关。上皮性卵巢癌组织中FLIP表达与PCNA表达成线性正相关,r分别0．880和0．564;FADD表达与PCNA表达成线性负相关,r分别为-0．591和-0．683。结论：FLIP、FADD与上皮性卵巢癌的发生发展密切相关,可能是治疗上皮性卵巢癌的潜在靶点。     

Current concepts in ovarian epithelial tumorigenesis: correlation between morphological and molecular data

Ovarian carcinoma is the most lethal gynaecological malignancy, most tumours being advanced at presentation. However, little is known about precursor lesions and the cell of origin of epithelial ovarian malignancy. In this review, the proposed cell of origin is discussed as well as recent molecular data relating to ovarian cancers of different morphological types. It is stressed that ovarian carcinoma is a heterogeneous group of neoplasms with several different morphological types, each with their own underlying molecular genetic events. Recent data suggest that mucinous ovarian cancers and a small subset of serous cancers (low grade ovarian serous carcinoma) develop through a well-defined adenoma-carcinoma sequence while the much more common high grade ovarian serous carcinoma develops de novo from the ovarian surface epithelium or the epithelium of cortical inclusion cysts. The realisation that various morphological types of epithelial ovarian cancer are associated with different molecular genetic events is a major advance in the study of ovarian cancer. It can be anticipated that this will lead to the development of specific therapeutic agents of value against a specific tumour type.     

用间期荧光原位杂交检测卵巢癌细胞中X染色体数目的异常

为了探讨用荧光原位杂交技术（fluorescence in situ hybridization, FISH）检测卵巢癌细胞中性染色体拷贝数目异常的实验方法及其应用价值,收集18例新鲜卵巢癌组织标本,以Biotin标记的X染色体α-卫星DNA（pBamX7）探针与经处理的标本进行卵巢癌细胞核的原位杂交,分别用Avidin-FITC和Anti-avidin进行信号的检测与放大,PI复染。于Olympus AX-70型荧光显微镜下,通过WIB滤光镜观察杂交信号及其细胞核背景,并统计卵巢癌细胞核中的杂交信号颗粒数量。在显微镜下可见以Biotin标记的pBamX7探针显示绿色杂交信号,细胞核背景经PI复染显示桔红色;发现11/18（61%）卵巢癌标本中X染色体拷贝数增加,其余7例（39%）无拷贝数增加。X染色体拷贝数目增多在卵巢癌中有一定比例的发生频率,其在促进卵巢癌发病及其发展过程中起到某种作用,其意义值得进一步研究。     

卵巢上皮性癌中干扰素介导的跨膜蛋白1的表达意义

目的:探讨干扰素介导的跨膜蛋白1(Interferon-induced transmembrane protein 1,IFITM1)基因在卵巢上皮性癌中表达的相关性及其意义。方法:应用Western blotting检测正常卵巢、卵巢良性肿瘤、卵巢交界性肿瘤和卵巢上皮性癌组织中IFITM1蛋白表达。免疫组织化学检测12例正常卵巢、21例卵巢良性肿瘤、18例卵巢交界性肿瘤和85例卵巢上皮性癌组织中IFITM1的蛋白表达,同时分析IFITM1表达状况与临床病理因素之间的相关性。结果:Western blotting显示卵巢上皮性癌和卵巢交界性肿瘤中IFITM1表达水平明显高于正常卵巢组织和卵巢良性肿瘤。免疫组化显示在正常卵巢组织中IFITM1阳性表达率为41.7%(5/12),在卵巢良性肿瘤组织中71.4%(15/21),在卵巢交界性肿瘤组织中为72.2%(13/18),在卵巢上皮性癌中为77.6%(66/85),IFITM1蛋白表达强度在正常卵巢、良性卵巢肿瘤、交界性卵巢肿瘤、上皮性卵巢癌间的比较有统计学意义(P0.05)。IFITM1蛋白表达与病理类型、肿瘤分化程度、肿瘤FIGO分期有关(P0.05),与淋巴结转移、腹水无明显相关性。化疗敏感组和耐药组的IFITM1表达强度间差异有统计学意义(P0.05)。结论:IFITM1在正常卵巢、卵巢良性肿瘤、卵巢交界性肿瘤和卵巢上皮性癌组织中的表达依次升高,并与卵巢癌以铂类为基础的化疗耐药性产生有相关性,为进一步研究IFITM1在卵巢癌诊治及化疗中的应用前景提供依据。     

HMGB1在卵巢癌中的表达及临床意义

目的:探讨高迁移率组蛋白B1(HMGB1)在卵巢癌患者血清及组织中的表达及临床意义。方法:采用ELISA技术检测96例女性血清中HMGB1水平,其中盆腔肿物住院患者66例按照术后病理结果分为卵巢良性肿瘤组40例和卵巢癌组26例,健康女性30例作为正常对照组,并通过免疫组织化学技术进一步检测卵巢癌、卵巢良性肿瘤组织中的表达情况。结果:卵巢癌组HMGB1水平明显高于其他两组,差异有统计学意义(P<0.05),正常对照组和卵巢良性肿瘤组比较差异无统计学意义(P>0.05)。结论:HMGB1测定有助于鉴别卵巢良恶性肿瘤。     

上皮性卵巢肿瘤组织MKP-1及p-ERK1/2蛋白表达的研究

研究丝裂原活化蛋白激酶（mitogen activated protein kinase, MAPK） 相关蛋白丝裂原活化蛋白激酶磷酸酶（mitogen activated protein kinase phosphatase-1, MKP-1）和磷酸化细胞外信号调节激酶（phosphorylation extracellular signal-regulated kinases, p-ERK1/2）曲在上皮性卵巢肿瘤组织及正常卵巢组织中的表达差异,并探讨其在卵巢癌发生、发展中的作用,为卵巢癌的治疗提供新的思路及实验依据。选取64例上皮性卵巢癌、35例卵巢上皮性交界瘤及32例卵巢上皮性良性肿瘤患者的组织,另选取26例正常卵巢组织作对照,进行MKP-1及p-ERK1/2的免疫组化分析,并同时对其中部分病例进行上述蛋白的Western—blot研究。结果显示正常卵巢、良性肿瘤、交界瘤及卵巢癌组织MKP—1的表达依次递减,各组之间进行两两比较均有显著性差异（P〈0．01）,FIGOⅢ期与Ⅳ期卵巢癌组织MKP-1的表达显著低于Ⅰ期与Ⅱ期卵巢癌组织（P〈0．01）;而p-ERK1/2在正常卵巢、良性肿瘤、交界瘤及卵巢癌组织的表达依次递增．各组之间进行两两比较也均有显著性差异（P〈0．01）。FIGOⅢ期与Ⅳ期卵巢癌组织P～ERK1/2的表达显著高于Ⅰ期与Ⅱ期卵巢癌组织（P〈0．01）。且免疫组化及western—blot均显示MKP-1与p—ERK1/2在卵巢癌组织中的表达存在显著的负相关性,（r=-0．90,P〈0．01及r=-0．78,P〈0．01）。本研究结果表明MKP-1与p—ERK1/2的异常表达可能跟上皮性卵巢肿瘤的发生、发展有关,它们之间的表达失衡可能是卵巢癌发生、发展的原因之一．     

Clinical Problems: Hypercalcaemia in Patients with Advanced Mammary Cancer

Hypercalcaemia and hypercalciuria are common complications of advanced mammary cancer. Of 127 patients with the disease 63 (49·5%) had some abnormality of calcium balance. Eighteen (14%) of these patients developed severe progressive hypercalcaemia and became acutely ill.Most patients had skeletal metastases, and the usual cause of hypercalcaemia was rapid destruction of bone by the cancer. One patient with severe uncontrollable hypercalcaemia and minimal skeletal involvement probably developed the complication due to inappropriate secretion of a parathyroid-hormone-like substance by massive hepatic deposits.Severe hypercalcaemia was controlled successfully in 13 of the 18 patients, the serum calcium levels returning to normal and the acute symptoms disappearing. Unfortunately, successful correction of the hypercalcaemia rarely was followed by prolonged survival from the underlying malignant disease. The incidence of subsequent objective response to pituitary ablation was less than usual, and only three patients survived for more than one year after the episode of hypercalcaemia.     

THE CONTROVERSIAL OVARY

Routine removal of ovaries at hysterectomy has been urged as a means of preventing ovarian carcinoma. Proponents of this policy, however, have not submitted the crucial datum: What proportion of women undergoing hysterectomy for benign conditions will later have ovarian carcinoma if the ovaries are not removed. Granting that oophorectomy will effectively prevent ovarian carcinoma, it creates an endocrine imbalance that cannot be corrected artificially, and the lack of ovarian hormones may precipitate osteoporosis or cardiovascular disease. If the ovaries appear normal, if there is no history of carcinoma, and if the patient understands and accepts the risk, the ovaries usually can be conserved at hysterectomy for benign conditions.     

The controversial ovary

Routine removal of ovaries at hysterectomy has been urged as a means of preventing ovarian carcinoma. Proponents of this policy, however, have not submitted the crucial datum: What proportion of women undergoing hysterectomy for benign conditions will later have ovarian carcinoma if the ovaries are not removed. Granting that oophorectomy will effectively prevent ovarian carcinoma, it creates an endocrine imbalance that cannot be corrected artificially, and the lack of ovarian hormones may precipitate osteoporosis or cardiovascular disease. If the ovaries appear normal, if there is no history of carcinoma, and if the patient understands and accepts the risk, the ovaries usually can be conserved at hysterectomy for benign conditions.     

Virus-augmented delayed hypersensitivity skin tests in gynecological malignancies

Summary Cultured human tumor cells of various histologic origins were infected with PR8/A/34 influenza virus. Nonviable crude membrane extracts were derived from the infected and uninfected cells. The extracts were coded and tested for their ability to produce delayed hypersensitivity skin reactions (DHSR) in allogeneic patients with squamous uterine cervical carcinoma, epithelial ovarian carcinoma, and malignant melanoma. Augmented antigen sensitivity to the virus-modified extracts compared with virus alone or to the unmodified extracts was observed in all patient groups. There was insufficient specificity to delineate a response by individual tumor type and related tumor extract, but some of the observed responses suggested tumor or organ site associations. Cervical carcinoma patients reacted more frequently to the virus-modified cervix extract, which also produced a high frequency of response in patients with ovarian carcinoma and melanoma. Ovarian carcinoma patients demonstrated increased sensitivity to both virus-modified ovarian carcinoma extracts, although 14 of 21 patients also showed responsiveness to one of the unmodified ovarian extracts. Malignant melanoma patients showed increased sensitivity to all virus-modified extracts except one of two derived from the ovarian carcinoma, and demonstrated a significantly augmented response to the virus-modified melanoma extract when the response to this extract was compared with that in ovarian carcinoma patients.The augmented reactions appear to be due to an association of the PR8 virus and as yet undetermined cellular components rather than to the virus alone. The possible involvement of tumor-associated determinants and the clinical significance of this phenomenon require further investigation.     

N-cadherin在卵巢癌中的表达及其临床病理意义

目的:探讨N-cadherin在人类卵巢癌组织中的表达及其临床-病理意义。方法:采用免疫组织化学染色法检测281例卵巢癌患者肿瘤组织中N-cadherin的表达,并分析其与患者临床病理特征之间的关系。结果:N-cadherin在卵巢癌原发灶中的表达显著低于配对的转移灶(P=0.018);卵巢癌组织中N-cadherin的表达与患者FIGO分期(P=0.034)、组织学类型(P0.001)、肿瘤分级(P=0.004)均显著相关。结论:N-cadherin高表达更多见于进展期(FIGOⅡ-Ⅳ)卵巢癌、高级别浆液性癌及高级别卵巢癌,可能与卵巢癌细胞的侵袭及迁移能力呈正相关,对判断卵巢癌的生物学行为具有重要的参考价值。     

Interaction between fortilin and transforming growth factor-beta stimulated clone-22 (TSC-22) prevents apoptosis via the destabilization of TSC-22

Yeast two-hybrid screening was conducted using a human ovary cDNA library to search for a novel binding protein using transforming growth factor-beta stimulated clone-22 (TSC-22). The selected protein was fortilin, which has been characterized as a nuclear anti-apoptotic protein. Overexpression of fortilin in ovarian carcinoma cells reversed TSC-22-mediated apoptosis, and the inhibition of fortilin expression via small interfering RNA (siRNA) resulted in an increase in the apoptosis of ovarian carcinoma cells. Moreover, fortilin overexpression promoted the degradation of TSC-22. Thus, an interaction between fortilin and TSC-22 prevents apoptosis via the destabilization of TSC-22 in ovarian carcinoma cells.     

Fractalkine receptor CX(3)CR1 is expressed in epithelial ovarian carcinoma cells and required for motility and adhesion to peritoneal mesothelial cells

Epithelial ovarian carcinoma (EOC) is a deadly disease, and little is known about the mechanisms underlying its metastatic progression. Using human specimens and established cell lines, we determined that the G-protein-coupled seven-transmembrane fractalkine receptor (CX(3)CR1) is expressed in primary and metastatic ovarian carcinoma cells. Ovarian carcinoma cells robustly migrated toward CX(3)CL1, a specific ligand of CX(3)CR1, in a CX(3)CR1-dependent manner. Silencing of CX(3)CR1 reduced migration toward human ovarian carcinoma ascites fluid by approximately 70%. Importantly, adhesion of ovarian carcinoma cells to human peritoneal mesothelial cells was dependent on CX(3)CL1/CX(3)CR1 signaling. In addition, CX(3)CL1 was able to induce cellular proliferation. Together, our data suggest that the fractalkine network may function as a major contributor to the progression of EOC, and further attention to its role in the metastasis of this deadly malignancy is warranted.     

Characterization of glycoconjugates released in vitro by human ovarian carcinoma cells isolated from effusions.

Ovarian carcinoma cell clusters were isolated from patient effusions. The glycoconjugates released to culture medium in vitro were characterized by electrophoretic, immunoassay and gel filtration procedures. Metabolically radiolabelled glycoconjugates were heterodisperse with respect to molecular weight and this heterodispersity was independent of incubation time in vitro. This heterodispersity was also characteristic of mixed Mullerian tumor cells of endometrial origin whereas mesothelial cells released a discrete glycoconjugate of MW 65-70 kDa. Multiple Coomassie blue-stained polypeptides were released by the carcinoma cells. These polypeptides were not adsorbed serum components as assessed by immunodiffusion analyses. Periodic acid-Schiff-reactive macromolecules appeared only at the top of electrophoresis gels. The high molecular weight glycoconjugates synthesized by ovarian carcinoma cells precipitated with an effusion globulin fraction at low ionic strength, but the low molecular weight components (40-70 kDa) were soluble. Immunoprecipitation with anti-Ig failed to precipitate carcinoma glycoconjugates. Antisera raised against the released carcinoma macromolecules precipitated carcinoma glycoconjugates and normal ovarian polypeptides. Antisera raised against normal ovarian macromolecules precipitated ovarian polypeptides but reacted only slightly with carcinoma glycoconjugates. Immunodiffusion analyses showed the presence of alpha 1-acid glycoprotein and carcinoembryonic antigen (CEA)-like components in the carcinoma glycoconjugates. The presence of CEA-like glycoconjugates was confirmed by immunoprecipitation. The antigens and antisera for different histologic types of ovarian carcinoma were cross-reactive. The presence of beta 2-microglobulin suggested that some of the glycoconjugates were shed from the cell surface.