Insulin-like growth factor expression in breast cancer epithelium and stroma

Summary The insulin-like growth factors (IGFs) are mitogens for many cancer cell types. In breast cancer cells, IGF-I and IGF-II have both been shown to stimulate cell proliferation. However, IGF-I mRNA has not been found in human breast cancer cell lines, making it unlikely that IGF-I is commonly expressed as an autocrine growth factor for breast cancer cells. Nevertheless, IGF-I mRNA can be detected in breast cancer tissue samples, and in situ hybridization studies have shown that the message originates from the stromal cells adjacent to normal lobules. IGF-II, on the other hand, has been detected in some breast cancer cell lines. In the estrogen receptor positive cell line T47-D, IGF-II mRNA was induced by estradiol. Furthermore, transfection of an IGF-II expression vector into a previously estrogen-dependent cell line resulted in hormone independent growth. Thus, IGF-II can be expressed as an autocrine growth factor in some breast cancers and its expression may, in part, result in hormone independence. Finally, stromal cells obtained from breast tissues showed that IGF-I was commonly expressed in fibroblasts derived from non-malignant biopsy specimens, while IGF-II mRNA was detected in fibroblasts adjacent to malignant tissue. These studies suggest that IGF-II expression may be important in both autocrine and paracrine regulation of breast cancer cell growth.     

Inhibition of fibroblast growth factors

Summary The potential roles of members of the fibroblast growth factor family in tumor angiogenesis and metastasis and their mechanisms of release from cells are discussed. Furthermore, we review methods of therapeutic targeting of these polypeptides. In particular, we focus on the possibility to inhibit fibroblast growth factors with drugs that mimic heparin-like cellular binding sites and thus can interfere with growth factor receptor recognition. In addition, we discuss antibodies, antisense oligodeoxynucleotides, and ribozymes as approaches to inhibit production and activity of these growth factors.List of abbreviations aFGF acidic fibroblast growth factor (=FGF-1) - bFGF basic FGF (=FGF-2) - HBGF heparin-binding growth factor - HGF hepatocyte growth factor - HSPG heparansulfate proteoglycan - PTN pleiotrophin - TGF transforming growth factor - VEGF vascular endothelial cell growth factor Presented at the symposium "New Approaches in the Therapy of Breast Cancer", Georgetown University Medical Center, Washington DC, October 1994, generously supported by an education grant from Bristol-Myers Squibb.     

Determination of epidermal growth factor receptor provides additional prognostic information to measuring tumor angiogenesis in breast carcinoma patients

Summary Recent studies have shown that women with invasive breast carcinoma having high microvessel density (MVD) (a measure of tumor angiogenesis) or epidermal growth factor receptor (EGFR) expression have increased risk for metastasis and/or decreased survival. To determine if MVD and EGFR expression provide additive prognostic information, we analyzed these two prognostic indicators in the primary invasive breast carcinomas from 165 consecutive patients, who were followed for a median of 51 months. Univariate analysis showed a highly significant (p<0.001) association of MVD with overall and relapse-free survival in all patients, including both node-negative and node-positive groups (see JNCI 84:1875–1887, 1992). For EGFR, although univariate analysis suggested that women with tumors showing EGFR expression relapsed earlier and, perhaps, died earlier, the differences were not statistically significant. Multivariate analysis, in contrast, revealed that determination of EGFR did provide significant additional information to that already provided by MVD for predicting relapse-free survival in all women (p=0.001) and in the subset of node-positive women (p=0.007). Among node-negative women, however, the contribution of EGFR expression in predicting relapse-free survival was not significant (p=0.12). Likewise, EGFR measurement did not provide significant additional information beyond that of MVD alone for predicting overall survival. Thus, EGFR provides additional prognostic information to determination of MVD, but only for relapse-free survival in node-positive women with invasive breast carcinoma.     

Fibroblast growth factor 8 is expressed at higher levels in lactating human breast and in breast cancer

Fibroblast growth factor 8 can transform NIH3T3 cells and its expression has been found to be associated with breast and prostate cancer. Following our finding that fibroblast growth factor 8 mRNA expression is increased in breast cancer, we have undertaken an immunohistochemistry study of fibroblast growth factor 8 expression in a series of human breast tissues and other normal tissues. Our findings confirm increased expression of fibroblast growth factor 8 in malignant breast tissue but also show significant fibroblast growth factor 8 expression in non-malignant breast epithelial cells. No significant difference in fibroblast growth factor 8 expression was found between different grades of ductal carcinoma, lobular carcinoma and ductal carcinoma in-situ or cancer of different oestrogen receptor, progesterone receptor or nodal status. The highest levels of fibroblast growth factor 8 expression were found in lactating breast tissues and fibroblast growth factor 8 was also detected in human milk. A survey of other normal tissues showed that fibroblast growth factor 8 is expressed in the proliferative cells of the dermis and epithelial cells in colon, ovary fallopian tube and uterus. Fibroblast growth factor 8 appears to be expressed in several organs in man and appears to have an importance in lactation.     

结缔组织生长因子与乳腺癌及其血管形成的关系

结缔组织生长因子是即刻早期反应基因的家族成员之一，CCN家族中富含半胱氨酸的外分泌型多肽，是转化生长因子β1的下游效应子，参与了血管平滑肌细胞和内皮细胞的生长、迁移，在创伤修复中参与了血管生成，但在肿瘤及其血管形成过程中的作用机制至今未明。乳腺组织中含有丰富的纤维结缔组织基质，尤其在乳腺癌中结缔组织生长因子含量明显增高，故它很可能参与了乳腺癌的各种生物学全过程。     

Extracellular matrix-resident growth factors and enzymes: possible involvement in tumor metastasis and angiogenesis

Summary Neoplastic cells require an appropriate pericellular environment and new formation of stroma and blood vessels in order to constitute a soilid tumor. Tumor progression also involves degradation of various extracellular matrix (ECM) constituents. In this review we have focused on the possible involvement of ECM-resident growth factors and enzymes in neovascularization and cell invasion. We demonstrate that the pluripotent angiogenic factor, basic fibroblast growth factor (bFGF) is an ECM component required for supporting cell proliferation and differentiation. Basic FGF has been identified in the subendothelial ECM producedin vitro and in basement membranes of the cornea and blood vesselsin vivo. Despite the ubiquitous presence of bFGF in normal tissues, endothelial cell (EC) proliferation in these tissues is usually very low, suggesting that bFGF is somehow sequestered from its site of action. Our results indicate that bFGF is bound to heparan sulfate (HS) in the ECM and is released in an active form when the ECM-HS is degraded by cellular heparanase. We propose that restriction of bFGF bioavailability by binding to ECM and local regulation of its release, provides a novel mechanism for regulation of capillary blood vessel growth in normal and pathological situations. Heparanase activity correlates with the metastatic potential of various tumor cells and heparanase inhibiting molecules markedly reduce the incidence of lung metastasis in experimental animals. Heparanase may therefore participate in both tumor cell invasion and angiogenesis through degradation of the ECM-HS and mobilization of ECM-resident EC growth factors. The subendothelial ECM contains also tissue type- and urokinase type- plasminogen activators (PA), as well as PA inhibitor which may regulate cell invasion and tissue remodeling. Heparanase and the ECM-resident PA participate synergistically in sequential degradation of HS-proteoglycans in the ECM. These results together with similar observations on the properties of other ECM-immobilized enzymes and growth factors, suggest that the ECM provides a storage depot for biologically active molecules which are thereby stabilized and protected. This may allow a more localized, regulated and persistent mode of action, as compared to the same molecules in a fluid phase.     

Inhibition of angiogenesis and growth of human non-malignant and malignant meningiomas by TNP-470

Summary Meningiomas are relatively common (22%) vascular brain tumors. 3–11% of meningiomas are malignant, and defy currently available therapy. Inhibition of neovascularization is one potential strategy for treating these hypervascular tumors. Inhibition of tumor-induced angiogenesis by TNP-470 (previously termed AGM-1470), a synthetic analogue of fumagillin, was tested on the growth of human non-malignant and malignant meningiomas in nude mice. TNP-470 significantly inhibited tumor neovascularization and tumor growth of both non-malignant and malignant meningiomas. TNP-470 is now in human trial and should be tested for efficacy in treating malignant or recurrent aggressive meningiomas.     

Fibroblast growth factor receptor promotes progression of cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte‐derived invasive and metastatic tumor of the skin. It is the second‐most commonly diagnosed form of skin cancer striking 200 000 Americans annually. Further, in organ transplant patients, there is a 65‐ to 100‐fold increased incidence of cSCC compared to the general population. Excision of cSCC of the head and neck results in significant facial disfigurement. Therefore, increased understanding of the mechanisms involved in the pathogeneses of cSCC could identify means to prevent, inhibit, and reverse this process. In our previous studies, inhibition of fibroblast growth factor receptor (FGFR) significantly decreased ultraviolet B‐induced epidermal hyperplasia and hyperproliferation in SKH‐1 mice, suggesting an important role for FGFR signaling in skin cancer development. However, the role of FGFR signaling in the progression of cSCC is not yet elucidated. Analysis of the expression of FGFR in cSCC cells and normal epidermal keratinocytes revealed protein overexpression and increased FGFR2 activation in cSCC cells compared to normal keratinocytes. Further, tumor cell‐specific overexpression of FGFR2 was detected in human cSCCs, whereas the expression of FGFR2 was low in premalignant lesions and normal skin. Pretreatment with the pan‐FGFR inhibitor; AZD4547 significantly decreased cSCC cell‐cycle traverse, proliferation, migration, and motility. Interestingly, AZD4547 also significantly downregulated mammalian target of rapamycin complex 1 and AKT activation in cSCC cells, suggesting an important role of these signaling pathways in FGFR‐mediated effects. To further bolster the in vitro studies, NOD.Cg‐Prkdcscid Il2rgtm1Wjl/SzJ mice with SCC12A tumor xenografts treated with AZD4547 (15 mg/kg/bw, twice weekly oral gavage) exhibited significantly decreased tumor volume compared to the vehicle‐only treatment group. The current studies provide mechanistic evidence for the role of FGFR and selectively FGFR2 in the early progression of cSCC and identifies FGFR as a putative therapeutic target in the treatment of skin cancer.     

Fibroblast growth factor-2, derived from cancer-associated fibroblasts,stimulates growth and progression of human breast cancer cells via FGFR1 signaling

Cancer-associated fibroblasts (CAFs) constitute a major compartment of the tumor microenvironment. In the present study, we investigated the role for CAFs in breast cancer progression and underlying molecular mechanisms. Human breast cancer MDA-MB-231 cells treated with the CAF-conditioned media manifested a more proliferative phenotype, as evidenced by enhanced messenger RNA (mRNA) expression of Cyclin D1, c-Myc, and proliferating cell nuclear antigen. Analysis of data from The Cancer Genome Atlas revealed that fibroblast growth factor-2 (FGF2) expression was well correlated with the presence of CAFs. We noticed that the mRNA level of FGF2 in CAFs was higher than that in normal fibroblasts. FGF2 exerts its biological effects through interaction with FGF receptor 1 (FGFR1). In the breast cancer tissue array, 42% estrogen receptor-negative patients coexpressed FGF2 and FGFR1, whereas only 19% estrogen receptor-positive patients exhibited coexpression. CAF-stimulated MDA-MB-231 cell migration and invasiveness were abolished when FGF2-neutralizing antibody was added to the conditioned media of CAFs. In a xenograft mouse model, coinjection of MDA-MB-231 cells with activated fibroblasts expressing FGF2 dramatically enhanced tumor growth, and this was abrogated by silencing of FGFR1 in cancer cells. In addition, treatment of MDA-MB-231 cells with FGF2 enhanced expression of Cyclin D1, a key molecule involved in cell cycle progression. FGF2-induced cell migration and upregulation of Cyclin D1 were abolished by siRNA-mediated FGFR1 silencing. Taken together, the above findings suggest that CAFs promote growth, migration and invasion of MDA-MB-231 cells via the paracrine FGF2-FGFR1 loop in the breast tumor microenvironment.     

Upregulation of basic fibroblast growth factor in breast carcinoma and its relationship to vascular density, oestrogen receptor, epidermal growth factor receptor and survival

Background: Angiogenesis, the process whereby endothelial cells divide and migrate to form new blood capillaries, has been assessed in tumours by measuring microvessel density. High microvessel density is a significant adverse prognostic factor in breast cancer. The angiogenic factor, basic fibroblast growth factor (bFGF), has been associated with tumourigenesis and metastasis in several human cancers. There are few quantitative studies of bFGF expression in normal tissues compared to cancer.Patients and methods: We have measured bFGF levels in 149 human primary breast carcinomas and assessed the findings in relation to microvessel density, oestrogen receptor (ER) and epidermal growth factor receptor (EGFR).Basic FGF levels were measured by ELISA. Western blotting and immunohistochemistry were carreid out to confirm the presence of bFGF.Results: Levels of bFGF were more than 10-fold higher in tumour cytosols compared to reduction mammoplasty tissue and 3-fold compared to non neoplastic cytosols from the same breast as the tumour (P < 0.0001). Immunohistochemistry showed bFGF protein was localised exclusively in the stroma whereas no bFGF staining was observed in the epithelial cells. High bFGF levels were significantly related to high ER (P = 0.01). Similarly, high bFGF levels were significantly related to low grade (P = 0.046) and to small tumour size (P = 0.04). No significant relationship was observed between bFGF and microvessel count, EGFR or age. In univariate analysis and in a Cox proportional hazard model bFGF did not reach significance for overall or relapse free survival.Conclusions: Our results show that although bFGF is elevated in breast carcinomas compared to normal breast tissue it is not related to microvessel density and it is not an independent predictor of survival in breast cancer patients. Basic FGF may be one of multiple factors that synergise with other growth factors such as VEGF to enhance angiogenesis.     

Paracrine growth regulation of human colon carcinoma organ-specific metastasis

Summary The process of cancer metastasis consists of a series of steps resulting in the spread of malignant cells beyond the site of origin and formation of metastases in distant organs. The outcome of this nonrandom process depends, in part, on the interaction of unique tumor cells with a compatible organ microenvironment. The molecular basis of the intrinsic capacity of distinct malignant cells to colonize specific organs and the degree to which host factors influence this process is under intense investigation. Biological analyses of human colon carcinoma tumors obtained from surgical specimens and implanted orthotopically into athymic nude mice revealed that these tumors are heterogeneous for metastatic properties. Moreover, recent evidence using this model suggest that whereas nonmetastatic and highly metastatic cells can grow at local sites, growth in the secondary liver-specific site was associated only with highly metastatic HCC cells. These cells also respond to mitogenic signals produced by damaged normal tissues, suggesting that physiological signals can be utilized by neoplastic cells. Molecular characterization of highly metastatic HCC cells selected in the nude mouse model as well asin situ mRNA hybridization of archival HCC surgical specimens for specific growth factor receptors correlated with the malignant cell's ability to respond to organ-specific growth factors. This article will focus on biological and molecular evidence supporting the hypothesis that organ-derived, paracrine growth factors regulate the site-specific growth of receptive malignant cells that possess the appropriate receptors.     

中国人群FGFR2基因多态性与乳腺癌易感相关性研究的Meta分析

目的系统评估成纤维细胞生长因子受体2(fibroblast growth factor receptor 2,FGFR2)基因内含子的3个单核苷酸位点rs2981582、rs1219648和rs2420946多态性与中国人群乳腺癌的易感性的关系。方法计算机检索PubMed、Embase、Cochrane library、中国知网、维普、万方数据库及中国生物医学文献数据库中,2014-06-01之前关于FGFR2基因内含子的3个单核苷酸位点rs2981582、rs1219648和rs2420946多态性与中国人群乳腺癌易感性的相关研究,按纳入与排除标准筛选文献、提取资料并评价纳入研究的质量后,采用Stata 12.0软件进行Meta分析,计算合并OR值及其95%CI,并进行发表偏倚评估及敏感性分析。结果共纳入18篇文献,包括14 568例患者和12 864名对照。Meta分析结果显示,FGFR2rs2981582、rs1219648和rs2420946基因多态性与中国人群乳腺癌有显著相关性。以地域进行亚组分析,rs2981582的T等位基因在南方人群(OR=1.13,95%CI:1.06~1.22,P=0.001)和北方人群(OR=1.26,95%CI:1.06~1.49,P=0.008)中与乳腺癌显著相关;rs2420946的T等位基因在南方人群(OR=1.15,95%CI:1.08~1.23,P<0.05)中与乳腺癌显著相关,北方人群中差异无统计学意义(OR=1.03,95%CI:0.87~1.22,P=0.695);rs1219648的G等位基因在南方人群(OR=1.19,95%CI:1.10~1.28,P<0.05)和北方人群(OR=1.17,95%CI:1.00~1.37,P=0.05)中与乳腺癌有显著相关。结论 FGFR2rs2981582、rs1219648和rs2420946基因多态性与中国人群乳腺癌易感性显著相关,但以地域进行亚组分析时则表现有差异。     

膀胱癌中bFGF和血管形成的研究

目的：探讨碱性成纤维细胞生长因子（ｂＦＧＦ）和血管形成与膀胱癌的发病及生物学行为之间关系。方法：采用免疫组化方法检测７２例膀胱癌组织和２１例正常膀胱组织中ｂＦＧＦ和第ＶＩＩＩ因子相关抗原表达。结果：膀胱癌组织中ｂＦＧＦ表达和微血管密度（ＭＶＤ）均显高于正常膀胱胱组织，而且两与肿瘤病理分级分期均密切相关。肿瘤复发的ｂＦＧＦ表达和ＭＶＤ均显高于复发，ｂＦＧＦ强阳性表达的ＭＶＤ值显高于阴性及弱阳性表达，结论：ｂＦＧＦ通过促进血管形成而在膀胱癌的发生发展过程中起着重要的作用，而且ｂＦＧＦ和ＭＶＤ可作为膀胱癌生物行为和预后的评估指标。     

血管内皮细胞生长因子的表达与肝细胞癌侵袭和转移的关系

目的了解血管内皮细胞生长因子（ＶＥＧＦ）ｍＲＮＡ在肝细胞癌（ＨＣＣ）和癌周组织中的表达,探讨ＶＥＧＦ与ＨＣＣ侵袭和转移的关系,为在分子水平干预肿瘤血管形成,预防ＨＣＣ复发和转移打下基础。方法采用逆转录—聚合酶链反应（ＲＴ－ＰＣＲ）检测方法,对４３例ＨＣＣ手术标本的癌和癌周组织中ＶＥＧＦｍＲＮＡ的表达水平进行了相对定量研究。结果肿瘤组织中ＶＥＧＦｍＲＮＡ的表达率为７９．１％（３４／４３）,癌周组织表达率仅为２０．９％（９／４３）;肿瘤组织中ＶＥＧＦｍＲＮＡ表达水平癌栓组（０．６９７９±０．２３６３）和包膜不完整组（０．４７０２±０．２８８３）分别显著高于无癌栓组（０．３４３６±０．２３９１）和包膜完整组（０．２８７０±０．２５１０,Ｐ＜０．０５）;肿瘤组织中ＶＥＧＦｍＲＮＡ表达水平大肝癌组（０．４０７２±０．２８８４）与小肝癌组（０．３７３４±０．２９００）相比差异无显著性（Ｐ＞０．０５）。结论ＶＥＧＦ在ＨＣＣ浸润和转移过程中发挥重要作用,肿瘤血管形成与ＨＣＣ浸润和转移关系密切。     

Paracrine and autocrine growth mechanisms in tumor metastasis to specific sites with particular emphasis on brain and lung metastasis

Once metastatic cells successfully seed at distant sites, their clinical detection and danger to the host are dependent on growth to form gross metastases. Metastatic tumor cells proliferate in response to local paracrine growth factors and inhibitors, and their growth also depends on production and responses to autocrine growth factors. A major organ-derived (paracrine) growth factor from lung tissue-conditioned medium has been isolated that differentially stimulates the growth of cells metastatic to brain or lung. Characterization of this mitogen demonstrated that it is a transferrin or a transferrin-like glycoprotein. Furthermore, antibodies to transferrin can remove significant growth activity from lung tissue-conditioned medium. Cells that are metastatic to brain or lung express greater numbers of transferrin receptors on their surfaces than cells that are poorly metastatic or metastatic to liver.Growth responses of metastatic cells and organ preferences of colonization appear to change during progression to more malignant states. At early stages of metastatic progression there is a tendency for many common malignancies to metastasize and grow preferentially at particular sites, suggesting that paracrine growth mechanisms may dominate the growth signals at this stage of progression. In contrast, at later stages of metastatic progression widespread dissemination to various tissues and organs occurs, and autocrine growth mechanisms may dominate the growth responses of metastatic cells. Ultimately, the progression of malignant cells to completely autonomous (acrine) states can occur, and at this stage of metastatic progression cell growth may be completely independent of autocrine and paracrine growth factors or inhibitors.     

Emmunohistochemical study on angiogenesis of axillary lymph node metastasis in human invasive breast carcinoma

The axially lymph node is one of the earliest and most common metastatic positions of breast carcinoma. Hence, axillary lymph node status (metastasis or no) and the number of metastatic lymph nodes are considered to be important indicators which affect prognosis of breast cancer patients. It has been widely confirmed that malignant solid tumor growth must be dependent upon angiogenesis/neovascularization. Considerable evidence has shown that microvessel density (MVD) of breast cancer tissue c…     

宫颈癌组织中Endoglin和VEGF表达与血管生成和癌细胞增殖及侵袭转移的关系

目的：探讨Endoglin和血管内皮生长因子（VEGF）在宫颈癌组织中的表达及意义。方法：采用免疫组织化学SP法检测75例宫颈癌（ICC）、18例宫颈上皮内瘤变（CIN）和15例正常宫颈上皮（NCE）组织中Endoglin和VEGF的表达情况,并检测其中微血管密度（MVD）（CD34标记）和Ki-67表达。结果：从NCE到CIN再到ICC,Endoglin和VEGF的阳性率显著升高,P〈0.05。Endoglin和VEGF在ICC组织中表达均与MVD显著正相关,P=0.000。Endoglin在ICC组织中表达与间质浸润深度和Ki-67表达有关,P〈0.05。ICC突破深肌层间质浸润和Ki-67高度表达者,其Endoglin阳性率分别显著高于未突破深肌层间质浸润和Ki-67表达在中度以内者,P〈0.05。VEGF在ICC组织中表达与盆腔淋巴结转移、脉管浸润、组织学分级及Ki-67表达有关,P〈0,05。ICC伴有盆腔淋巴结转移、脉管浸润、组织学分级为Ⅲ级及Ki-67高度表达者,其VEGF阳性率分别显著高于无盆腔淋巴结转移、无脉管浸润、组织学分级在Ⅱ级以内及Ki-67表达在中度以内者,P〈0.05。Endoglin在ICC组织中表达与VEGF显著正相关,P=0.021。宫颈癌Endoglin和VEGF均阳性表达者,其Ki-67高度表达率及MVD均显著高于两者均阴性表达者,P〈0.05。结论：宫颈癌组织Endoglin和VEGF均过度表达,其血管生成显著增加,癌细胞增殖活跃,更易发生侵袭转移。     

Involvement of epidermal growth factor receptor overexpression in the promotion of breast cancer brain metastasis

BACKGROUND:

Brain‐metastatic breast cancer (BMBC) is increasing and poses a severe clinical problem because of the lack of effective treatments and because the underlying molecular mechanisms are largely unknown. Recent work has demonstrated that deregulation of epidermal growth factor receptor (EGFR) may correlate with BMBC progression. However, the exact contribution that EGFR makes to BMBC remains unclear.

METHODS:

The role of EGFR in BMBC was explored by serial analyses in a brain‐trophic clone of human MDA‐MB‐231 breast carcinoma cells (231‐BR cells). EGFR expression was inhibited by stable short‐hairpin RNA transfection or by the kinase inhibitor erlotinib, and it was activated by heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF). Cell growth and invasion activities also were analyzed in vitro and in vivo.

RESULTS:

EGFR inhibition or activation strongly affected 231‐BR cell migration/invasion activities as assessed by an adhesion assay, a wound‐healing assay, a Boyden chamber invasion assay, and cytoskeleton staining. Also, EGFR inhibition significantly decreased brain metastases of 231‐BR cells in vivo. Surprisingly, changes to EGFR expression affected cell proliferation activities less significantly as determined by a 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay, an anchorage‐independent growth assay, and cell cycle analysis. Immunoblot analysis suggested that EGFR drives cells' invasiveness capability mainly through phosphoinositide 3‐kinase/protein kinase B and phospholipase C γ downstream pathways. In addition, EGFR was involved less in proliferation because of the insensitivity of the downstream mitogen‐activated protein kinase pathway.

CONCLUSIONS:

The current results indicated that EGFR plays more important roles in cell migration and invasion to the brain than in cell proliferation progression on 231‐BR cells, providing new evidence of the potential value of EGFR inhibition in treating BMBC. Cancer 2012. © 2012 American Cancer Society.     

微血管密度和血管内皮生长因子与大肠癌肝转移的关系研究

目的研究微血管密度(MVD)和血管内皮生长因子(VEGF)与大肠癌术后发生肝转移的关系。方法检测160例大肠癌标本中VEGF、和MVD的表达并结合随访结果。结果 VEGF、和MVD与大肠癌的临床分期密切相关:Duke C期的vEGF和MVD表达高于B期,差异有显著性(p<0.01);术后发生肝转移组VEGF和MVD表达高于无转移组,差异有显著性(P<0.01)。结论检测大肠癌病灶中MVD和VEGF的表达能预测患者的临床分期,MVD和VEGF过度表达的患者,术后发生肝转移的危险性大。     

Role of transforming growth factor beta in the growth inhibition of human breast cancer cells by basic fibroblast growth factor

Recent studies from our laboratory have revealed that basic fibroblast growth factor (bFGF) selectively inhibits the proliferation of human MCF-7 breast cancer cells. It has also been shown to enhance cis-platinum-induced apoptosis, decrease levels of the anti-apoptotic gene product bcl-2, and increase levels of the cyclin-dependent protein kinase inhibitor p21/WAF1/Cip1. Transforming growth factor beta-1 (TGF₁), a cell growth regulator has been found to have an inhibitory effect on breast cancer cells. The aim of the present study was to evaluate the possible role of TGF₁ in the antiproliferative effects of bFGF in MCF-7 breast cancer cells. We found that exogenous, as well as endogenous (overexpressed) bFGF increased TGF₁ mRNA expression in the cells and enhanced the secretion of TGF₁ into culture medium. However, exogenous addition of TGF₁ neither led to a decrease in bcl-2 nor induced an increase in the levels of p21/WAF1/Cip1 and neutralizing antibodies to TGF₁, did not reverse bFGF-induced G₁ arrest nor the increase in p21/WAF1/Cip1 level. In contrast, antisense oligonucleotides to TGF₁ abrogated the antiproliferative effects and inhibited the induction of p21/WAF1/Cip1 by bFGF in MCF-7 cells. These data suggest that the anti-proliferative effects of bFGF in human MCF-7 breast cancer cells are mediated by endogenous TGF₁, while exogenous TGF₁ does not mimic all the effects of bFGF on these breast cancer cells. These findings provide an important basis for further investigations into the autocrine and paracrine processes that control the growth of breast cancer cells.