Expression of heparin-binding epidermal growth factor-like growth factor in breast carcinoma

The expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF) was investigated for 76 cases of breast carcinoma. HB-EGF was expressed in 71.8% of the carcinoma cases but only slightly in normal mammary glands. Interestingly, its expression was inversely related to biological aggressiveness of the breast carcinoma. These results suggest that HB-EGF may play a crucial role in the early stage of this carcinoma.     

Significance of the expression of the growth factor pleiotrophin in pancreatic cancer patients.

PURPOSE: Recently, we found that pleiotrophin (PTN) acts as a rate-limiting autocrine growth factor in pancreatic cancer cells. The aim of this study was to determine the expression pattern of PTN in pancreatic cancer and to analyze the clinical significance of PTN in pancreatic cancer patients. EXPERIMENTAL DESIGN: We compared PTN expression in malignant (n = 24), inflammatory (n = 13), and normal (n = 14) pancreatic tissues using immunohistochemistry and in situ hybridization and determined PTN serum levels in pancreatic cancer patients (n = 77), in patients suffering from chronic pancreatitis (n = 21), and in healthy volunteers (n = 28). Two-year survival rates were determined for pancreatic cancer patients in relation to serum levels of PTN. RESULTS: The frequency of PTN expression increased from normal tissue (7%) to inflammatory (34%) and pancreatic cancer tissues (67%; P < 0.05). Compared with a healthy control group, we found elevated PTN serum levels in 30% of patients with chronic pancreatitis (mean, 143 +/- 55 pg/ml) and in 53% of pancreatic cancer patients (mean, 200 +/- 29 pg/ml; P < 0.05). Elevated serum levels of PTN dropped in patients after successful tumor resection but were unaffected when only palliative surgery was performed (P < 0.0001). High preoperative serum PTN levels correlated with a worse 2-year survival (P < 0.05). CONCLUSIONS: This study supports the clinical significance of PTN for the malignant progression of pancreatic cancer.     

Nerve growth factor is a potential therapeutic target in breast cancer

We show here that nerve growth factor (NGF), the prototypic neurotrophin, can be targeted in breast cancer to inhibit tumor cell proliferation, survival, and metastasis. Analysis of a series of biopsies revealed widespread expression of NGF in the majority of human breast tumors, with anti-NGF immunoreactivity concentrated in the epithelial cancer cells. Moreover, immunodeficient mice xenografted with human breast cancer cells and treated with either anti-NGF antibodies or small interfering RNA against NGF displayed inhibited tumor growth and metastasis. Such treatments directed against NGF induced a decrease in cell proliferation with a concomitant increase in apoptosis of breast cancer cells and an inhibition of tumor angiogenesis. Together, these data indicate that targeting NGF in breast cancer may have therapeutic ramifications.     

The role of growth factors in breast cancer

A series of teleconferences has been organized under the auspices of Bristol-Myers to address several major current questions in oncology. A panel of recognized experts with a moderator has been assembled to discuss each question, and we are reporting a number of these discussions in Breast Cancer Research and Treatment. This is reprinted from Oncology Viewpoints, courtesy of Bristol-Myers Oncology Division, Evansville IN 47721, USA.     

Clinical significance of heparin-binding epidermal growth factor-like growth factor in peritoneal fluid of ovarian cancer

Epidermal growth factor receptor (EGFR) has been implicated in tumour growth and extension of ovarian cancer. Peritoneal fluid in ovarian cancer patients contains various growth factors that can promote tumour growth and extension. In order to investigate the clinical significance of EGFR ligands as activating factors of ovarian cancer, we examined the cell proliferation-promoting activity and the level of EGFR ligands in peritoneal fluid obtained from 99 patients. Proliferation-promoting activity in peritoneal fluid from 63 ovarian cancer patients (OVCA) was much higher than peritoneal fluid from 18 ovarian cyst patients (OVC) and 18 normal ovary patients (NO), and the activity was suppressed only by antibodies against EGFR or heparin-binding epidermal growth factor (HB-EGF). A large difference was observed in the level of EGFR ligands between HB-EGF and TGF-alpha or amphiregulin. The concentration of HB-EGF in OVCA significantly increased compared to that in OVC or NO (P<0.01). No significant difference in the concentration of TGF-alpha and amphiregulin was found between the OVCA and NO or OVC groups. In peritoneal fluid, HB-EGF is sufficiently elevated to activate cancer cells even at an early stage of OVCA. These results suggested that HB-EGF in peritoneal fluid might play a key role in cell survival and in the proliferation of OVCA.     

A potential autocrine role for vascular endothelial growth factor in prostate cancer

Vascular endothelial growth factor (VEGF) is a peptide growth factor specific for the tyrosine kinase receptors VEGF receptor-1 and -2 (VEGFR-1 and R-2). Whereas VEGF has well-defined actions on the vasculature, including the stimulation of endothelial cell growth and motility and blood vessel permeability, the function of the VEGF/receptor pathway in other cell types is largely unknown. Recently, VEGFR-1 and R-2 expression has been reported in prostate tumor cells. In this study, we demonstrate that these receptors colocalize with VEGF in prostate tumor cells, prostatic intraepithelial neoplasia, and the basal cells of normal glands. Furthermore, in comparison with normal glands, the expression of VEGFR-1 and R-2 is increased in prostatic intraepithelial neoplasia and malignant cells in well and moderately differentiated prostate cancer but is decreased in poorly differentiated cancer. Culture of the prostate cancer cell line LNCaP in the presence of recombinant human VEGF165 resulted in a 50% increase in [(3)H]thymidine uptake by these cells and recruitment of quiescent cells into the cell cycle. This effect of recombinant human VEGF165 was abolished by neutralizing antisera to VEGFR-2. These data suggest that VEGF may not only mediate neovascularization associated with prostate cancer progression but may also directly stimulate prostate tumor cells via VEGFR-2-dependent autocrine and/or paracrine mechanisms.     

The potential and actual growth rate of breast cancer

Potential and actual rates of tumor growth were assayed in 13 patients with primary breast cancer. Potential growth rate was calculated according to proliferative activity as assessed by histoautoradiography whereas actual growth--on the basis of changes in tumor size observed on mammograms obtained through the course of the disease. Actual tumor doubling time proved 22.8 times longer (which means that tumors grew slower) than that suggested by proliferative activity. Cell loss at the average rate of 95.5% proved the main reason accounting for the difference. The proliferative activity in regional lymph node metastases measured in 3 patients simultaneously with the primary tumor assay was 3.9 times higher.     

Epidermal growth factor receptor as a potential therapeutic target in triple-negative breast cancer

BackgroundNo proven targeted therapy is currently available for the treatment of triple-negative breast cancer (TNBC). Epidermal growth factor receptor (EGFR) is frequently overexpressed in TNBC. We studied the activity of EGFR antagonists alone, and in combination with chemotherapy, in TNBC cell lines.Materials and methodsEGFR and phosphorylated EGFR were measured by enzyme-linked immunosorbent assay. Sensitivity to EGFR inhibitors alone and in combination with chemotherapy was assessed. Effects of gefitinib on EGFR signalling and cell cycle were also examined.ResultsEGFR was overexpressed in the TNBC compared with the human epidermal growth factor receptor 2 (HER-2)-positive cell lines. Phosphorylation of EGFR was detected in the TNBC cells in response to epidermal growth factor stimulation and was blocked by gefitinib treatment. However, the TNBC cell lines were less sensitive to EGFR inhibition than the HER-2-positive cell lines. Response to gefitinib was associated with reduced phosphorylation of both mitogen activated protein kinase (MAPK) and Akt and induction of G₁ arrest. Gefitinib enhanced response to both carboplatin and docetaxel in the TNBC cells, and the triple combination of gefitinib, carboplatin and docetaxel was synergistic.ConclusionsAlthough the TNBC cells are less sensitive to EGFR inhibition than the HER-2-positive cell lines, gefitinib enhanced response to chemotherapy. Gefitinib combined with carboplatin and docetaxel warrants further investigation in TNBC.     

萝卜硫素在乳腺癌、卵巢癌及宫颈癌中的潜在作用

随着医学对硫代葡萄糖苷在植物中积累的遗传和环境因素的了解以及对这些化合物及其衍生物作用认识的增加,人们对硫代葡萄糖苷及其产物可能的作用研究也有了重大进展,作为饮食的一部分时,其可以降低肿瘤和心脏病的风险。研究发现,这些生物活性物质与传统的抗肿瘤治疗方法结合起来,可以提高抗肿瘤治疗的效果。萝卜硫素是一种同源异硫氰酸酯,主要存在于芸薹属蔬菜中,其摄入与乳腺癌、卵巢癌等肿瘤的发生呈显著负相关,可能是通过提高细胞的解毒能力和抗氧化能力外,萝卜硫素还可以调节细胞的生长,这对于肿瘤预防尤其重要。萝卜硫素的细胞抑制和细胞毒性作用机制包括诱导细胞凋亡、抑制细胞周期进程和抑制血管生成,靶向肿瘤细胞关键细胞信号通路的多个位点,发挥类似靶向药物的抗肿瘤作用。本篇综述通过介绍萝卜硫素在乳腺癌、卵巢癌及宫颈癌辅助化疗和放疗疗效的可能机制,为其在乳腺癌、卵巢癌及宫颈癌临床上的应用提供理论线索。     

The role of prolactin and growth hormone in breast cancer

This review will focus on the role for prolactin (PRL) and growth hormone (GH) in mammary tumor formation. Much attention has previously been focused on circulating levels of GH/PRL in relation to mammary tumor formation. We will review data demonstrating that these ligands also could be produced locally in different organs, including the mammary gland and mammary tumors, and suggest that this local production may be of importance for pathological conditions. We will also discuss mechanisms for crosstalk between steroids and GH/PRL. A crosstalk between GH- and PRL response is possible at multiple levels. In the human, GH can activate both the prolactin receptor (PRLR) and the growth hormone receptor (GHR). We have demonstrated that activation of the PRLR, but not the GHR, is inducing mammary tumors in transgenic mice. Furthermore, the elevated levels of insulin-like growth factor 1 (IGF-I) seen in the GHR activating transgenic mice is not sufficient for tumor induction. The induced tumors express functionally active prolactin that could be of importance for the tumor formation. Paracrine/aurocrine stimulation by PRL may be more important than PRL transported via the circulation. In women, the role for stimulation of the PRLR and/or the GHR in mammary tumor formation has not been proven, although experiments from primates suggest that the PRLR could be of importance.     

Enhanced levels of Hsulf-1 interfere with heparin-binding growth factor signaling in pancreatic cancer

   

Hsulf-1 is a newly identified enzyme, which has the ability to decrease the growth of hepatocellular, ovarian, and head and neck squamous cell carcinoma cells by interfering with heparin-binding growth factor signaling. Since pancreatic cancers over-express a number of heparin-binding growth factors and their receptors, the expression and function of this enzyme in pancreatic cancer was analyzed.     

Significance of the association between heparin-binding epidermal growth factor-like growth factor and CD9 in human gastric cancer

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the EGF family. Juxtacrine activity of proHB-EGF (the membrane-anchored form of HB-EGF) has been shown to be significantly potentiated when it is coexpressed with CD9 in vitro. The purpose of our study was to investigate the issue of whether proHB-EGF and CD9 are coexpressed in gastric cancer. HB-EGF gene expression and protein production in human gastric cancers was investigated, and EGF receptor and CD9 expressions were also evaluated. HB-EGF mRNA levels in gastric cancers were elevated, compared with normal gastric tissues, especially in the intestinal type. ProHB-EGF immunoreactivity was detected primarily in the cytoplasm and plasma membrane of gastric cancer cells. Of 66 patients, 40 (60.6%) exhibited proHB-EGF immunoreactivity and the level of its expression was significantly associated with tumor status (p < 0.01) and histological differentiation (p < 0.001). In addition, proHB-EGF mRNA was detected at high levels in the intestinal type by in situ hybridization. CD9 immunoreactivity was found to be preserved in 26 of 36 patients (72.2%) and CD9 protein expression was inversely associated with lymph node status (p < 0.05). A significant correlation between its expression and histological differentiation (p < 0.01) was found, and the association of CD9 with proHB-EGF was increased in the intestinal type, as evidenced by an immunoprecipitation method. These results indicate that the coexpression of proHB-EGF and CD9 may be involved in the tumorigenesis and/or proliferation of gastric cancers in a juxtacrine manner.     

Transforming growth factor beta: potential autocrine growth inhibitor of estrogen receptor-negative human breast cancer cells

Transforming growth factor beta (TGF beta), a two-subunit Mr 25,000 polypeptide, inhibits growth of several epithelial human cancer cell lines and has been proposed as an autocrine growth inhibitor. TGF beta activity has been found in conditioned media from some breast cancer cell lines, and TGF beta mRNA has been detected in breast cancer cell lines and human breast cancer specimens. In the present study we attempted to characterize the interaction of TGF beta with breast cancer cells by examining the biological activity, receptor binding, and secretion of this polypeptide by a panel of estrogen receptor (ER)-positive and ER-negative human breast cancer cell lines. Growth of the four ER-negative lines, MDA231, MDA330, HS578T, and BT20, was exquisitely sensitive to TGF beta. Dose-dependent inhibition of monolayer growth, anchorage-independent growth, and of [3H]thymidine incorporation was observed with TGF beta concentrations ranging from 1 to 100 pM. Growth of the four ER-positive lines, T47D, ZR75-1, and two MCF7 lines from different laboratories, was unaffected by similar concentrations of TGF beta. In receptor-binding studies using 125I-TGF beta, the four ER-negative lines exhibited specific high affinity TGF beta receptors. Binding was a time- and temperature-dependent process. Scatchard analysis of the binding data showed between 2800 and 12900 receptor sites per cell and a Kd between 29 and 160 pM. Epidermal growth factor, insulin, insulin-like growth factors I and II, and transforming growth factor alpha did not compete for 125I-TGF beta binding. Chemical cross-linking studies with ER-negative breast cancer cells revealed three specific TGF beta receptors with molecular weights approximating 400,000, 92,000, and 69,000. The four ER-positive lines had no detectable TGF beta binding. Using a radioreceptor assay with A549 cells and a NRK bioassay, TGF beta activity was detectable in the conditioned media from the four ER-negative cell lines; media from the ER-positive lines had low levels of TGF beta activity. In summary, ER-negative, estrogen-independent cultured human breast cancer cells have receptors for, are inhibited by, and secrete TGF beta activity, suggesting the possibility that this polypeptide may function as an autocrine growth inhibitor or as a paracrine growth factor for tumor stromal cells.     

The role of growth factor receptor pathways in human breast cancer cells adapted to long-term estrogen deprivation

To study the long-term effects of estrogen deprivation on breast cancer, MCF-7Ca human estrogen receptor-positive breast cancer cells stably transfected with human aromatase gene were cultured in the steroid-depleted medium for 6 to 8 months until they had acquired the ability to grow. Proliferation of these cells (UMB-1Ca) was accompanied by increased expression of human epidermal growth factor receptor 2, increased activation of AKT through phosphorylation at Ser473 and Thr308, and increased invasion compared with parental MCF-7Ca cells. Estrogen receptor expression was also increased 5-fold. Although growth was inhibited by the antiestrogen fulvestrant, the IC50 was 100-fold higher than for parental MCF-7Ca cells. Aromatase inhibitor letrozole also inhibited growth at 10,000-fold higher concentration than required for MCF-7Ca cells, whereas anastrozole, exemestane, formestane, and tamoxifen were ineffective at 100 nmol/L. Growth of UMB-1Ca cells was inhibited by phosphatidylinositol 3-kinase inhibitor wortmannin (IC50 approximately 25 nmol/L) and epidermal growth factor receptor kinase inhibitor gefitinib (ZD 1839; IC50 approximately 10 micromol/L) whereas parental MCF-7Ca cells were insensitive to these agents. Concomitant treatment of UMB-1Ca cells with the signal transduction inhibitors and anastrozole and tamoxifen restored their growth inhibitory effects. These studies show that estrogen deprivation results in up-regulation of growth factor signaling pathways, which leads to a more aggressive and hormone refractory phenotype. Cross-talk between ER and growth factor signaling was evident as inhibition of these pathways could restore estrogen responsiveness to these cells.     

成纤维细胞生长因子受体3在乳腺癌中的研究进展

成纤维细胞生长因子受体3（FGFR3）在调节细胞的增殖、分化及血管形成中发挥重要作用。近年来,研究发现 FGFR3在乳腺癌发生发展和内分泌治疗耐药性乳腺癌中发挥一定的作用,并且与乳腺癌患者的预后密切相关。