CD105 Expression on CD34-Negative Spindle-Shaped Stromal Cells of Primary Tumor Is an Unfavorable Prognostic Marker in Early Breast Cancer Patients

Several studies have confirmed that the breast tumor microenvironment drives cancer progression and metastatic development. The aim of our research was to investigate the prognostic significance of the breast tumor microenvironment in untreated early breast cancer patients. Therefore, we analyzed the association of the expression of α-SMA, FSP, CD105 and CD146 in CD34-negative spindle-shaped stromal cells, not associated with the vasculature, in primary breast tumors with classical prognostic marker levels, metastatic recurrence, local relapse, disease-free survival, metastasis-free survival and the overall survival of patients. In the same way, we evaluated the association of the amount of intra-tumor stroma, fibroblasts, collagen deposition, lymphocytic infiltration and myxoid changes in these samples with the clinical-pathological data previously described. This study is the first to demonstrate the high CD105 expression in this stromal cell type as a possible independent marker of unfavorable prognosis in early breast cancer patients. Our study suggests that this new finding can be useful prognostic marker in the clinical-pathological routine.     

KIT (CD117) Expression in a Subset of Non-Small Cell Lung Carcinoma (NSCLC) Patients

We have previously described the expression of CD44, CD90, CD117 and CD133 in NSCLC tumors, adjacent normal lung, and malignant pleural effusions (MPE). Here we describe the unique subset of tumors expressing CD117 (KIT), a potential therapeutic target. Tumor and adjacent tissue were collected from 58 patients. Six MPE were obtained before therapy. Tissue was paraffin embedded for immunofluorescent microscopy, disaggregated and stained for flow cytometry or cryopreserved for later culture. The effect of imatinib on CD117^high/KIT+ tumors was determined on first passage cells; absolute cell counts and flow cytometry were readouts for drug sensitivity of cell subsets. Primary tumors divided into KIT^neg and KIT⁺ by immunofluorescence. By more sensitive flow cytometric analysis, CD117+ cytokeratin+ cells were detected in all tissues (1.1% of cytokeratin+ cells in normal lung, 1.29% in KIT “negative” tumors, 40.7% in KIT⁺ tumors, and 0.4% in MPE). In KIT⁺/CD117^high, but not KIT⁺/CD117^low tumors, CD117 was overexpressed 3.1-fold compared to normal lung. Primary cultures of CD117^high tumors were sensitive to imatinib (5 µM) in short term culture. We conclude that NSCLC tumors divide into CD117^low and CD117^high. Overexpression of CD117 in CD117^high NSCLC supports exploring KIT as a therapeutic target in this subset of patients.     

CD117、CD34、DOG-1、WT-1 在胃肠道间质瘤中的表达及意义

目的:探讨DOG-1、CD117、CD34、WT-1在胃肠道间质瘤(GIST)中的表达及临床意义。方法:应用免疫组织化学SP法检测DOG-1、CD117、CD34、WT-1在39例GIST患者肿瘤组织中的表达。结果:GIST光镜下主要由梭形细胞和(或)上皮样细胞或多形性细胞混合或单一性组成。DOG-1、CD117、CD34和WT-1在GIST肿瘤组织中阳性表达率分别为92.3%(36/39)、71.7%(28/39)、64.1%(25/39)、23.1%(9/39),四者的阳性表达率在各风险程度组(极低及低度危险性GIST、中度危险性GIST、高度危险性GIST)两两比较中差异均无统计学意义(P>0.05)。DOG-1与CD117相比,在极低及低度危险组中表达有显著差异(P<0.05),DOG-1与CD34相比,在极低及低度危险组、高度危险组中表达有显著差异(P<0.05);WT-1与CD117相比,在中度及高度危险组中表达有显著差异(P<0.05),WT-1与CD34相比,在中度危险组中表达有显著差异(P<0.05)。对照组平滑肌瘤、纤维瘤、神经鞘瘤中CD117、DOG-1在GIST中的表达明显高于其他多种梭形细胞的表达(P<0.05)。结论:DOG1是GIST较为敏感和特异的标记物,WT-1在极低及低度危险性GIST中有一定的诊断价值,在GIST的诊断中加入两者将使患者更加受益。     

CD31和CD105在卵巢上皮性肿瘤中的表达及其临床病理意义

目的探讨CD31和CD105在卵巢上皮性肿瘤及正常卵巢组织中的表达情况及其与卵巢肿瘤生物学行为之间的关系,并比较同为肿瘤血管内皮标记物的CD31和CDl05在标记微血管方面的差异。方法收集天津市肿瘤医院临床、病理和预后资料完整的恶性卵巢上皮性肿瘤组织标本76例,病例标本采用免疫组化EnVision法检测CD31和CD105所标记的MVD数值,MVD计数参照Weidner方法进行量化分析,实验同时取20例交界性卵巢上皮性肿瘤、10例良性卵巢上皮性肿瘤和10例宫颈癌手术中切除的正常卵巢组织作为对照。结果①CD31蛋白在卵巢上皮性肿瘤的微血管和大血管上均有较强表达,在正常卵巢组织血管中亦有表达,恶性卵巢肿瘤中的MVD-CD31值（5．484-_0．75）显著高于交界性卵巢肿瘤（2．24±0．61）、良性卵巢肿瘤（2．24土0．41）及正常卵巢组织（1．20±0．37）（P〈0．01）;在卵巢癌中,MVD-CD31值仅与有无淋巴结转移及组织学分级之间的差异有统计学意义（P〈O．05）,而与年龄、病理类型、肿瘤大小、腹水、有无远处转移无关（P〉0．05）。②CDl05蛋白在卵巢肿瘤微血管中有表达,在正常卵巢组织中呈微弱表达或无表达,恶性卵巢肿瘤中的MVD-CDl05值（4．07士2．11）显著高于交界性卵巢肿瘤（2．08土0．30）、良性卵巢肿瘤（1．92±1．15）及正常卵巢组织（O．68±0．39）（P〈0．05或P〈0．01）;在卵巢癌中MV口CDl05值与组织学分级、有无腹水、有无远处转移、有无淋巴结转移有关（P〈0．05）,而与年龄、病理类型、肿瘤大小等因素无关（P〉0．05）。③恶性肿瘤组织中的MVD-CD31值显著高于MVD-CDl05值（P〈0．05）。结论在标染卵巢癌方面,CDl05比CD31有明显优越性,CDl05的表达与卵巢癌的生物学行为密切相关,MVD-CDl05值的检测可更准确的确定肿瘤的临床分期、指导治疗及判断预后。     

上皮性卵巢癌患者血清 microRNA-21 的水平及其临床意义研究

目的:检测上皮性卵巢癌患者血清中microRNA-21的表达,并探讨其作为标记物预测上皮性卵巢癌化疗耐药患者预后的可行性。方法:采用探针型实时荧光定量逆转录聚合酶链反应检测和比较20例上皮性卵巢癌患者和10例正常人卵巢血清标本中microRNA-21的表达,并分析血清microRNA-21水平与上皮性卵巢癌患者化疗耐药及其临床病理特征的相关性。结果:正常人、上皮性卵巢癌化疗敏感和化疗耐药患者血清中micro RNA-21的相对表达量分别为0.573±0.318、2.606±1.057、26.766±26.710,上皮性卵巢癌化疗敏感和化疗耐药患者血清中miR-21的相对表达量均显著高于正常人血清中miR-21的相对表达量(P<0.05),而上皮性卵巢癌化疗耐药患者血清中miR-21表达显著高于上皮性卵巢癌化疗敏感患者,差异有统计学意义(P<0.05)。上皮性卵巢癌化疗耐药患者血清miR-21表达水平与其手术-病理分期无及是否发生淋巴结转移均无明显相关性(P>0.05)。结论:上皮性卵巢癌患者血清microRNA-21水平显著升高,可能作为其化疗耐药的预测参考指标,但血清microRNA-21水平与上皮性卵巢癌化疗耐药患者的不良预后并无显著相关性。     

转录因子FOXM1在上皮性卵巢癌中的表达及临床意义

FOXM1(Forkhead box protein M1)是调控细胞增殖的重要转录因子,近年来研究表明与肿瘤发生密切相关,但与卵巢癌的关系尚不明确.通过检测68例卵巢癌标本、21例卵巢良性肿瘤标本、24例正常卵巢标本以及3株卵巢癌细胞系(A2780细胞、OVCAR3细胞、SKOV3细胞)中FOXM1的表达情况,分析其与临床参数之间的相关性及临床意义.结果显示卵巢癌中FOXM1表达明显高于卵巢良性肿瘤及正常卵巢组织,差异极为显著,其中低分化细胞中表达强于中高分化细胞(P=0.013),Ⅲ～Ⅳ期表达强于Ⅰ～Ⅱ期(P=0.011),但与病理类型无关;FOXM1在3株卵巢癌细胞系中均有较强表达.FOXM1在卵巢癌组织及3种卵巢癌细胞系中存在高表达,且与卵巢癌分化程度及临床分期有关.     

环氧合酶-2在卵巢癌中的表达及其临床意义

目的：探讨COX-2的表达与卵巢癌生物学关系。方法：采用免疫组化SP法,分别测定12例正常卵巢组织、16例良性卵巢肿瘤、70例卵巢癌组织中COX-2的表达。结果：70例卵巢癌组织中COX-2阳性表达62例,明显高于正常卵巢组织,COX-2与临床分期、及淋巴结转移均有一定关系,与病理类型无关。结论：COX-2与卵巢癌的发生、发展及转移有关,可作为观察卵巢癌进展的重要指标。     

MicroRNA-141 在上皮性卵巢癌患者组织和血清中的表达 及临床意义的探讨

目的:探讨微小RNA-141(miR-141)在卵巢癌患者组织和血清中的表达情况并初步探讨其作为肿瘤标记物早期诊断上皮性卵巢癌的可行性。方法:采用实时荧光定量逆转录聚合酶链反应(real-time RT-PCR)检测16例上皮性卵巢癌患者和4例正常人卵巢组织及血清标本中miR-141的表达;检测4例良性卵巢肿瘤血清中miR-141的表达。结果:miR-141在卵巢癌患者组织中相对表达量分别为(72.846±76.671)显著高于正常人(2.869±3.201)(P<0.05);miR-141在卵巢癌患者血清中相对表达量(31.581±52.885)显著高于良性卵巢肿瘤患者(0.668±1.196)和正常人(1.690±1.697)(P<0.05),后两组间表达无差异(P>0.05);miR-141表达随卵巢癌临床分期的进展呈上升趋势(P<0.01),在无淋巴结转移组明显高于有淋巴结转移组(P<0.05),与组织分级和CA125的升高无关(P>0.05)。在组织中miR-141表达水平与上皮性卵巢癌临床病理特征均未见明显差异(P>0.05)。结论:miR-141可能在上皮性卵巢癌的发生发展中发挥癌基因的作用;miR-141用于检测上皮性卵巢癌敏感性和特异度较高,有望成为上皮性卵巢癌早期诊断的新指标。     

MicroRNA-141在上皮性卵巢癌患者组织和血清中的表达及临床意义的探讨

目的：探讨微小RNA-141（miR-141）在卵巢癌患者组织和血清中的表达情况并初步探讨其作为肿瘤标记物早期诊断上皮性卵巢癌的可行性。方法：采用实时荧光定量逆转录聚合酶链反应（real-timeRT—PCR）检测16例上皮性卵巢癌患者和4例正常人卵巢组织及血清标本中miR-141的表达;检测4例良性卵巢肿瘤血清中miR-141的表达。结果：miR-141在卵巢癌患者组织中相对表达量分别为（72．846±76．671）显著高于正常人（2．869±3．201）（P〈0．05）;miR-141在卵巢癌患者血清中相对表达量（31．581±52．885）显著高于良性卵巢肿瘤患者（0．668±1．196）和正常人（1．690±1．697）（P〈0．05）,后两组间表达无差异（P〉0．05）;miR-141表达随卵巢癌临床分期的进展呈上升趋势（P〈0．01）,在无淋巴结转移组明显高于有淋巴结转移组（P〈0．05）,与组织分级和CA125的升高无关（P〉0．05）。在组织中miR-141表达水平与上皮性卵巢癌临床病理特征均未见明显差异（P〉0．05）。结论：miR-141可能在上皮性卵巢癌的发生发展中发挥癌基因的作用;miR-141用于检测上皮性卵巢癌敏感性和特异度较高,有望成为上皮性卵巢癌早期诊断的新指标。     

Increased Expression of CAP2 Indicates Poor Prognosis in Hepatocellular Carcinoma

CAP2 has been suggested as a potential diagnostic biomarker for early hepatocellular carcinoma (HCC). However, its prognostic significance in HCC remains unclear. Here, we show that CAP2 expression is much higher in HCC tissues than that in paracarcinoma tissues, at both mRNA and protein levels. Data of immunohistochemistry (IHC) revealed that CAP2 was markedly up-regulated in 77.3% of HCC cases. High CAP2 expression, defined by the median score of IHC, was present in 53.3% of the patients. Kaplan-Meier analysis indicated that high CAP2 expression was associated with poor overall survival (P < .0001), disease-free survival (P = .013) and recurrence probability (P = .004) in a training cohort of 312 HCC patients. The prognostic implication of CAP2 in HCC was further confirmed in a validation cohort of 208 HCC patients and by stratified survival analysis. Multiple Cox regression analysis indicated CAP2 as an independent predictor for overall survival (hazard ratio (HR) = 1.615, 95% confidence interval: 1.345-1.938, P < .001). Collectively, we conclude that CAP2 is increased in HCC and is a novel unfavorable biomarker for prognostic prediction for patients with this deadly disease.     

CD56和CD117浆细胞免疫表型与多发性骨髓瘤患者染色体核型和预后的研究

目的:探讨CD56和CD117浆细胞免疫表型与多发性骨髓瘤患者染色体核型和预后的关系。方法:选取2011年1月至2017年3月我院收治的66例多发性骨髓瘤患者,均采用以硼替佐米为基础的VTD化疗方法。采集患者新鲜骨髓液,采用流式细胞术(FCM)和荧光原位杂交技术(FISH)检测浆细胞免疫表型和细胞染色体核型。分析浆细胞免疫表型与患者染色体核型和预后的关系。结果:66例患者浆细胞CD19+、CD20+、CD45+、CD56+、CD117+表达频率分别为7.6%(5/66)、18.2%(12/66)、45.5%(30/66)、66.7%(44/66)和40.9%(27/66)。20例行FISH检测的患者,18例(90.0%)核型异常,其中12例(66.7%)IgH重排,9例(50.0%)1q21+扩增,8例(44.4%)del(13q14.3)缺失,10例(55.6%)del(13q14)缺失,3例(16.7%)del(17p)缺失。CD56+患者1q21+扩增和del(13q14.3)发生率显著低于CD56-患者(27.3%vs 85.7%,18.2%vs 85.7%,P0.05)。CD117+患者1q21+扩增和del(17p)发生率显著低于CD117-患者(12.5%vs 80.0%,12.5%vs 20.0%,P0.05)。CD56+患者的PFS和OS明显延长[23.4(2.0-91.4)月vs 19.8(3.0-85.1)月,34.5(8.9-96.5)月vs 30.1(6.7-84.3)月,P0.05]。CD117+患者PFS和OS明显延长[22.9(1.0-94.3)月vs 20.3(2.0-84.3)月,33.9(7.4-93.5)月vs 31.4(6.7-89.7)月,P0.05]。Kaplan-Meier分析CD56和CD117阳性与阴性患者的PFS曲线和OS曲线存在显著性差异(P0.05)。结论:CD56+和CD117+患者的预后明显优于CD56-和CD117-患者,CD56-和CD117-患者染色体异常核型的发生率明显增加。     

Aberrant Expression of Osteopontin and E-Cadherin Indicates Radiation Resistance and Poor Prognosis for Patients with Cervical Carcinoma

Radiotherapy is the first-line treatment for all stages of cervical cancer, whether it is used for radical or palliative therapy. However, radioresistance of cervical cancer remains a major therapeutic problem. Consequently, we explored if E-cadherin (a marker of epithelial-mesenchymal transition) and osteopontin could predict radioresistance in patients with locally advanced cervical squamous cell carcinoma (LACSCC). Patients were retrospectively reviewed and 111 patients divided into two groups (radiation-resistant and radiation-sensitive groups) according to progression-free survival (PFS). In pretreated paraffin-embedded tissues, we evaluated E-cadherin and osteopontin expression using immunohistochemical staining. The percentage of patients with high osteopontin but low E-cadherin expression in the radiation-resistant group was significantly higher than those in the radiation-sensitive group (p<0.001). These patients also had a lower 5-year PFS rate (p<0.001). Our research suggests that high osteopontin but low E-cadherin expression can be considered as a negative, independent prognostic factor in patients with LACSCC ([Hazard ratios (95% CI) 6.766 (2.940, 15.572)], p<0.001).     

Oncologic Trogocytosis of an Original Stromal Cells Induces Chemoresistance of Ovarian Tumours

Background

The microenvironment plays a major role in the onset and progression of metastasis. Epithelial ovarian cancer (EOC) tends to metastasize to the peritoneal cavity where interactions within the microenvironment might lead to chemoresistance. Mesothelial cells are important actors of the peritoneal homeostasis; we determined their role in the acquisition of chemoresistance of ovarian tumours.

Methodology/Principal Findings

We isolated an original type of stromal cells, referred to as “Hospicells” from ascitis of patients with ovarian carcinosis using limiting dilution. We studied their ability to confer chemoresistance through heterocellular interactions. These stromal cells displayed a new phenotype with positive immunostaining for CD9, CD10, CD29, CD146, CD166 and Multi drug resistance protein. They preferentially interacted with epithelial ovarian cancer cells. This interaction induced chemoresistance to platin and taxans with the implication of multi-drug resistance proteins. This contact enabled EOC cells to capture patches of the Hospicells membrane through oncologic trogocytosis, therefore acquiring their functional P-gp proteins and thus developing chemoresistance. Presence of Hospicells on ovarian cancer tissue micro-array from patients with neo-adjuvant chemotherapy was also significantly associated to chemoresistance.

Conclusions/Significance

This is the first report of trogocytosis occurring between a cancer cell and an original type of stromal cell. This interaction induced autonomous acquisition of chemoresistance. The presence of stromal cells within patient''s tumour might be predictive of chemoresistance. The specific interaction between cancer cells and stromal cells might be targeted during chemotherapy.     

原发性肝细胞癌组织中Beclin 1的表达及其意义

目的：探讨原发性肝细胞癌（HCC）组织中Beclin 1的表达及其在肝细胞癌发生发展中的作用。方法：应用免疫组化EnVision法检测54例肝细胞癌组织及其癌旁组织中Beclin 1的表达,分析其与肝细胞癌的病理分级、临床分期、侵袭及转移等临床病理因素的关系。结果：HCC组织中Beclin 1阳性表达率明显低于癌旁组织（X2=7.53,P〈0.01）。病理分级Ⅲ～Ⅳ、TNM分期Ⅲ～Ⅳ、存在静脉浸润和淋巴结转移的肝癌组织中的Beclin 1表达水平明显低于病理分级Ⅰ～Ⅱ、TNM分期Ⅰ～Ⅱ、无静脉浸润和淋巴结转移的肝癌组织（P〈0.01）。结论：HCC组织中存在Beclin 1表达缺失,可能与HCC的发生有着密切的关系,且对HCC的恶性生物学行为有重要影响。     

CD4+CD25hiCD127low Regulatory T Cells Are Increased in Oral Squamous Cell Carcinoma Patients

Regulatory T cells (Tregs), a subset of CD4⁺ T cells plays a pivotal role in regulating the immune system. An increase in Treg numbers enables cancer progression by dampening the immune system and allowing tumor cells to evade immune detection and destruction. An increase in Treg numbers and expression of inhibitory cytokines including TGF-β and IL-10 are mechanisms by which Tregs exert their immune suppressive function. However, the presence of Tregs and inhibitory cytokines in oral cancer patients is still unclear. In this study, the presence of circulating Tregs in 39 oral cancer patients and 24 healthy donors was examined by studying the presence of the CD4⁺CD25^hiCD127^low cell population in their peripheral blood mononuclear cells using flow cytometry. Serum levels of TGF-β and IL-10 were measured by ELISA. T cell subsets of OSCC patients were found to differ significantly from healthy donors where a decrease in CD8⁺ cytotoxic T cells and an increase in Tregs (CD4⁺CD25^hiCD127^low) were observed. Further, the ratio of CD8⁺ T cells/Tregs was also decreased in patients compared to healthy donors. The presence of Tregs was accompanied by a decrease in IL-10 but not TGF-β secretion in OSCC patients when compared to donors; in addition, the analysis also revealed that an increased presence of Tregs was accompanied by better patient survival. Amongst OSCC patients, smokers had significantly higher levels of TGF-β. It is apparent that the immune system is compromised in OSCC patients and the characterization of the Treg subpopulation could form a basis for improving our understanding of the perturbations in the immune system that occur during OSCC tumorigenesis.     

Variable Stromal Periductular Expression of CD34 and Smooth Muscle Actin (SMA) in Intraductal Carcinoma of the Breast

In breast carcinoma, the stromal loss of CD34 expression and acquisition of SMA myofibroblastic features may constitute a prerequisite for tumor invasiveness. However, this hypothesis remains controversial, with some authors describing the loss of CD34 fibrocytes in the absence of SMA myofibroblastic-like cells in the stroma of invasive carcinoma. Others have also described the disappearance of CD34 fibrocytes from in situ carcinoma. To clarify this issue, we compared the distribution of CD34 fibrocytes and SMA reactive myofibroblasts between stromal areas of tumor-free mammary tissue, ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC). In addition to 28 IDC, 300 normal duct–lobular units and 600 ducts with DCIS (158 low-grade, 266 intermediate, and 176 high-grade) were scored. The relationships between staining patterns and different histological features (grade of DCIS and presence or absence of necrosis) were compared. Loss of CD34 expression and acquisition of SMA expression were more frequent in high-grade in situ lesions than in intermediate and low-grade lesions (p<0.001). When necrosis was found in association with grade 2 or 3 DCIS, the decrease in CD34 expression was higher than in lesions without necrosis and that independently of the grade of DCIS (p<0.05). Necrosis did not appear to play a significant role in the expression of SMA (p = 0.35). In all cases, the stroma of invasive carcinomas showed a complete loss of CD34 fibrocytes. Future research on both CD34 fibrocytes and mechanisms stromal changes are essential in the future and may potentially lead to new treatment approaches.     

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。