Targeting chemotherapy-induced PTX3 in tumor stroma to prevent the progression of drug-resistant cancers

The tumor microenvironment has been suggested to participate in tumorigenesis, but the nature of the communication between cancer cells and the microenvironment, especially in response to anticancer drugs, remains obscure. We determined that activation of the CCAAT/enhancer binding protein delta (CEBPD) response to Cisplatin and 5-Fluorouracil in cancer-associated macrophages and fibroblasts contributed to the metastasis, invasion, acquired chemoresistance and stemness of cancer cells by in vitro and in vivo assays. Specifically, reporter and in vivo DNA binding assays were used to determine that Pentraxin 3 (PTX3) is a CEBPD responsive gene and serves a protumor role upon anticancer drug treatment. Finally, a PTX3 peptide inhibitor RI37 was developed and assessed the antitumor effects by in vivo assays. RI37 could function as a promising inhibitor for preventing cancer progression and the metastasis, invasion and progression of drug-resistant cancers. The identification of PTX3 provided a new insight in the interaction between host and tumor and the RI37 peptide showed a great opportunity to largely reduce the risk of invasion and metastasis of cancer and drug-resistant cancers.     

Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium.

The present study demonstrates that fibroblasts associated with carcinomas stimulate tumor progression of initiated nontumorigenic epithelial cells both in an in vivo tissue recombination system and in an in vitro coculture system. Human prostatic carcinoma-associated fibroblasts grown with initiated human prostatic epithelial cells dramatically stimulated growth and altered histology of the epithelial population. This effect was not detected when normal prostatic fibroblasts were grown with the initiated epithelial cells under the same experimental conditions. In contrast, carcinoma-associated fibroblasts did not affect growth of normal human prostatic epithelial cells under identical conditions. From these data, we conclude that in this human prostate cancer model, carcinoma-associated fibroblasts stimulate progression of tumorigenesis. Thus, carcinoma-associated fibroblasts can direct tumor progression of an initiated prostate epithelial cell.     

Phenotypic dynamics of tumor progression in human malignant melanoma

The phenotypic changes in human melanoma cells during the course of tumor progression were studied with monoclonal antibodies (MAbs) against the melanoma-associated antigens (MAA) M.2.2.4, H.2.8.10, K.1.2, A.1.43, and A.10.33, and HLA-(A,B,C and D). Cryostat sections of 172 primary melanomas of the skin, 157 melanoma metastases and 56 nevi were investigated with an indirect immunoperoxidase method. Phenotypic heterogeneity was observed within lesions at all stages, and also within different tumors of the same patients. Despite this heterogeneity, principles of antigen expression were found. From the reaction pattern of MAbs, the following classifications of antigens were derived: "constitutive" markers of nevomelanocytic cells (M.2.2.4 and H.2.8.10) were found expressed over a wide range of local and systemic tumors. One MAA, K.1.2 (Suter et al., 1985), that declines with progression of melanoma, was classified as an "early" antigen, whereas MAA that appear in primary melanoma in proportion to invasiveness, and which are expressed in metastases of lymph nodes and visceral organs (A.1.43, and A.10.33), were classified as "late" markers of tumor progression. HLA-antigens were classified as "intermediate" markers, HLA-A,B,C, as an "early-intermediate", and HLA-DR as a "late-intermediate" marker. The occurrence of class II HLA, A.1.43-, and A.10.33-positive tumor cells in primary melanoma indicates a high metastatic potential of tumors, independent of tumor thickness. The data show that local and systemic progression of melanoma is associated with qualitative changes in tumor cells which can be recognized by MAbs.     

Autophagic tumor stroma: Mechanisms and roles in tumor growth and progression

Macroautophagy (hereafter autophagy) is a cellular homeostatic mechanism that involves protein and organelle degradation, and has a number of connections to human physiology and diseases. Autophagy in tumor parenchyma acts as either a tumor‐promoting role or a tumor‐inhibiting role depending on the types and stages of tumors. In recent years, attention to autophagy in tumor stroma that is referred as “autophagic tumor stroma” has created a new paradigm to understand the role of autophagy in cancer. Here we propose that the autophagic tumor stroma is a phenomenon of adaptation at a certain stage of tumor development, and has a prominent role in tumor growth, progression and spread of tumors. This idea is supported by recent studies: (i) Autophagic tumor stroma is activated by hypoxia and cancer cells induced oxidative stress, when tumors grow to a certain stage; (ii) Autophagic tumor stroma aids in providing essential nutrients to malignant cells, remodeling the tumor microenvironment, increasing DNA damage, genetic instability and stemness in cancer cells, and decreasing the apoptotic sensitivity of cancer cells. The autophagic tumor stroma is therefore a significant determinant in tumor growth and progression and implicates an important target for cancer therapies.     

Loss of heterozygosity involves multiple tumor suppressor genes in human esophageal cancers.

Loss of heterozygosity occurring on various chromosomes has been described in the majority of human tumors. The targets of frequent or consistent subchromosomal deletions are believed to be tumor suppressor genes. We examined 72 esophageal tumors (46 squamous cell carcinomas and 26 adenocarcinomas) for loss of heterozygosity at the p53, Rb, APC, MCC, and DCC loci. Inclusion of these tumor suppressor genes in the allelic deletions was directly ascertained by performing polymerase chain reaction at polymorphic sites within the genes. Loss of heterozygosity occurred in 55% of informative cases at p53, in 48% of informative cases at Rb, in 66% at APC, in 63% at MCC, and in 24% at DCC. Ninety-three % of tumors informative at all loci (fully informative) lost heterozygosity of at least one locus. A high percentage of fully informative tumors (71%) also lost heterozygosity at more than one locus. There were no significant differences among histological types in the prevalence of loss of heterozygosity at any locus. There were correlations of losses involving MCC versus DCC, Rb, and p53. These data suggest that (a) allelic deletions including these tumor suppressor genes are important in the formation and/or progression of most esophageal cancers; (b) allelic deletions involving MCC may not occur independently of deletions involving other tumor suppressor genes; and (c) the accumulation of multiple allelic deletions involving specific tumor suppressor genes may be important in most esophageal tumorigenesis or tumor evolution.     

Expression of aromatase in tumor related stroma is associated with human bladder cancer progression

Putative gender differences in bladder cancer (BCa) have been proposed to result from sex hormone influence. Aromatase is the key enzyme catalyzing the conversion of androgens to estrogens which may result in an intratumoral microenviroment with increased estrogen production. In this study, we investigated the expression pattern of aromatase and its association with BCa progression. Tissue samples from 88 BCa patients who underwent cystectomy were obtained. Using immunohistochemistry (IHC), expression of aromatase in tumor epithelium (TE) and tumor related stroma (TS) were evaluated separately, and the association of aromatase expression status with pathologic variables and overall survival (OS) outcome was examined. High aromatase expression was found in 33/88 (37.5%) of TE and in 65/88 (73.9%) of TS. Increased aromatase expression in TE had a trend to correlate with male gender. Increased aromatase in TS was significantly associated with adverse pathologic variables including higher pathologic pT, positive lymph node metastasis (pN), lymphovascular invasion (LVI), and distant metastasis. In univariate analysis, high aromatase expression in TS was significantly associated with poorer overall survival (p = 0.014), but this association was not significant (p = 0.163) in multivariate cox analysis adjusted for independent factors including age at surgery and pN. These results demonstrate that aromatase expression in TS but not TE may play a critical role in BCa progression. Our findings provide direct evidence of aromatase involvement in BCa and suggest endocrine therapy may have a potential role in the treatment of BCa.     

Spontaneous fusion with, and transformation of mouse stroma by, malignant human breast cancer epithelium

Adenocarcinoma cells from the pleural effusion of a patient with breast cancer were injected into the mammary glands of nude mice and grown into solid tumors. A cell line derived from these tumors expressed alpha-smooth muscle actin but not human cytokeratin 7, indicating "activated" stroma of mouse origin. Cells in mitosis exhibited mainly polyploid mouse karyotypes, but 30% had mixed mouse and human chromosomes, among which 8% carried mouse/human translocations. Nuclei of interphase cells were 64% hybrid. Hybrid mouse/human nuclei were also detected in the primary xenograft. Thus, synkaryons formed in the solid tumor by spontaneous fusion between the malignant human epithelium and the surrounding normal host mouse stroma. The transformed stroma-derived cells are tumorigenic with histopathologic features of malignancy, suggesting a new mechanism for tumor progression.     

细胞内氯离子通道蛋白4与恶性肿瘤发生发展的研究进展

细胞内氯离子通道蛋白4(chloride intracellular channel 4,CLIC4)是细胞内氯离子通道家族成员之一,广泛分布于细胞内,定位于多种细胞器如线粒体、内质网及细胞核和细胞质中,在多种肿瘤组织中表达异常,与肿瘤细胞的黏附、分化、凋亡等生物学行为密切相关,研究其在肿瘤发生、发展过程中的具体作用,将为多种肿瘤的诊断、治疗及预后提供新的依据。     

Loss of NKX3.1 expression in human prostate cancers correlates with tumor progression

NKX3.1 is a prostate-specific homeobox gene located on chromosome 8p21. In the mouse, Nkx3.1 has growth-suppressive and differentiating effects on prostatic epithelium. Mutations of the coding region of NKX3.1 were not found in human prostate cancer, failing to support the notion that NKX3.1 was a tumor suppressor gene. To study the expression o NKX3.1 protein in human tissues and prostate cancer, we derived a rabbit antiserum against purified recombinant NKX3.1. Among normal human tissues, NKX3.1 expression was seen in testis, in rare pulmonary mucous glands, and in isolated regions of transitional epithelium of the ureter. NKX3.1 was uniformly expressed in nuclei of normal prostate epithelial cells in 61 histological sections from radical prostatectomy specimens. We analyzed 507 samples of neoplastic prostate epithelium, most of which were contained on a tissue microarray that contained samples from different stages of prostatic neoplasia. We observed complete loss of NKX3.1 expression in 5% of benign prostatic hyperplasias, 20% of high-grade prostatic intraepithelial neoplasias, 6% of T1a/b samples, 22% of T3/4 samples, 34% of hormone-refractory prostate cancers, and 78% of metastases. Our data show that NKX3.1 expression is highly, but not exclusively, specific for the prostate. Loss of NKX3.1 expression is strongly associated with hormone-refractory disease and advanced tumor stage in prostate cancer (P < 0.0001).     

Syk在不同组织来源的人腺上皮恶性肿瘤中的表达

目的：探讨不同组织来源的人腺上皮恶性肿瘤细胞中Syk的表达,分析其临床意义。方法：应用免疫组织化学染色法分别检测7种人腺上皮恶性肿瘤细胞株、30例人乳腺癌组织及其35例人胰腺癌组织中Syk的表达。结果：人乳腺癌细胞株MCF-7中Syk表达阳性,MDA-MB-231则表达阴性；人胰腺癌细胞株PANC-1、SW1990和Canpan-2,人肺腺癌细胞株GLC-82和肝癌细胞株SMMC-7721中Syk均表达阳性。30例乳腺癌组织及其癌旁正常组织中Syk表达阳性率分别为60% (18/30)和90%(27/30),两者之间有显著性差异(P＜0．01)。22例胰腺癌组织及其癌旁正常组织中Syk表达阳性率分别54．5%(12/22)和86．3%(19/22),两者之间有显著性差异(P＜0．01)；13例经术前化疗的胰腺癌组织及其癌旁正常组织中Syk表达阳性率分别为69．2%(9/13)和92．3%(12/13),两者之间有显著性差异(P＜0．01)。结论：Syk在所检测的不同组织来源的人腺上皮恶性肿瘤细胞株中绝大部分(6/7)呈阳性表达；Syk蛋白在乳腺、胰腺正常组织中高表达,在相应肿瘤组织中低表达或不表达的特性,Syk有可能成为乳腺癌患者的预后判定、治疗计划的制定等较为特异性指标。     

Porous silicon nanocarriers for dual targeting tumor associated endothelial cells and macrophages in stroma of orthotopic human pancreatic cancers

Pancreatic cancer is a highly fatal disease characterized by a dominant stroma formation. Exploring new biological targets, specifically those overexpressed in stroma cells, holds significant potential for the design of specific nanocarriers to attain homing of therapeutic and imaging agents to the tumor. In clinical specimens of pancreatic cancer, we found increased expression of CD59 in tumor associated endothelial cells as well as infiltrating cells in the stroma as compared to uninvolved pancreas. We explored this dual targeting effect using orthotopic human pancreatic cancer in nude mice. By immunofluorescence analysis, we confirmed the increased expression of Ly6C, mouse homolog of CD59, in tumor associated endothelial cells as well as in macrophages within the stroma. We decorated the surface of porous silicon nanocarriers with Ly6C antibody. Targeted nanocarriers injected intravenously accumulated to tumor associated endothelial cells within 15 min. At 4 h after administration, 9.8 ± 2.3% of injected dose/g tumor of the Ly6C targeting nanocarriers accumulated in the pancreatic tumors as opposed to 0.5 ± 1.8% with non-targeted nanocarriers. These results suggest that Ly6C (or CD59) can serve as a novel dual target to deliver therapeutic agents to the stroma of pancreatic tumors.     

Oncogene amplification in neoplastic development and progression of human cancers

Increased dosage of cellular oncogenes resulting from amplification of DNA is a frequent genetic abnormality of tumor cells. Certain types of human tumors carry a specific amplified cellular oncogene at frequencies of up to 50 to 60%. Human neuroblastoma has been prototypic for a contribution of amplification to tumorigenesis, and evidence is emerging that amplification may be an early event involved in a malignant form of this cancer. It is unclear at which stage amplification plays a role in other cancers. Amplification of cellular oncogenes is a good predictor for clinical outcome in some human malignancies and is a paradigm for the application of oncogene research in a clinical context.     

炎症——肿瘤恶性演进的推手

越来越多的证据表明,炎性微环境在肿瘤的发生、发展中发挥着重要的促进作用,炎性因子介导的信号通路参与了肿瘤细胞的恶性演进。细胞上皮-间质转型（epithelial-mesenchymal transition, EMT）是肿瘤恶性演进过程中的关键机制,炎性细胞因子（白细胞介素、TNF-α、TGF-β等）、EMT的关键转录因子\[锌指E盒结合同源盒蛋白（zinc finger E-box-binding homeobox, ZEB）、Snail和Twist等\]及某些miRNA（let-7、miR-200等）共同构成复杂的调控网络,调控肿瘤细胞的表型转化、药物抗性的产生、肿瘤干细胞（cancer stem cell, CSC）的增殖及自我更新。本文将重点讨论炎症及相关信号通路在肿瘤发生、发展以及CSC形成过程中的调控机制。     

Skp2在人类恶性肿瘤中的研究进展

Skp2是泛素连接酶复合物的底物识别序列,对正常细胞周期起调控作用,在多数恶性肿瘤中表达增高.研究发现Skp2与肿瘤的预后、恶性进程、治疗均有密切关系.现就Skp2与恶性肿瘤的关系作一综述.     

Tritiated thymidine labeling index of benign and malignant human breast epithelium.

38 specimens of benign breast tissue from young women and 92 primary breast carcinomas were evaluated for tritiated thymidine ([3H]TdR) labeling index (TLI) by in vitro pulse labeling. The TLI on nonneoplastic, terminal breast ducts was significantly higher during the latter half than during the first half of the menstrual cycle (P less than 0.001), and a geometric mean TLI of 1.5 during the latter half of the cycle is consistent with approximately 47% turnover of these cells during the menstrual cycle. Ducts of fibroadenomas showed similar menstrual variation TLI. The range of TLI observed in the carcinomas was 0.04-18.6, arithmetic mean 3.7, geometric mean 2.1. The TLI of carcinomas was not significantly correlated with size of the tumor, but tended to be higher in women less than 50 yr old than in women older than 50 yr (P less than 0.05), and in the presence of two or more metastatic axillary lymph nodes than when fewer than two nodes were involved (P less than 0.02).     

上皮-间质转化及相关microRNA分子与肿瘤的恶性行为的研究进展

上皮-间质转化(epithelial-mesenchymal transition,EMT)是上皮细胞表型向间质细胞表型转变的过程,是一种重要的病理生理现象,与肿瘤侵袭、转移及耐药等恶性行为密切相关;microRNA作为一种与基因转录调控有关的重要小分子RNA,在EMT过程中有着举足轻重的作用.本研究就EMT现象及相关microRNA 分子与肿瘤恶性行为的研究进展作一综述.