Luteinizing hormone-releasing hormone agonist triptorelin antagonizes signal transduction and mitogenic activity of epidermal growth factor in human ovarian and endometrial cancer cell lines

This study was designed to elucidate the signal transduction mechanisms, mediating the antiproliferative effects of analogs of luteinizing hormone releasing hormone (LHRH) on cell lines derived from human cancers of the ovary (EFO-21, EFO-27) and the endometrium (HEC-1A, Ishikawa). The LHRH agonist triptorelin had no measurable effects on the activity of phospholipase C, protein kinase C, or adenylate cyclase in all 4 cell lines, though these enzymes could be activated through pharmacological stimuli. The proliferation of EFO-21, EFO-27 and HEC-1A cells in serum/phenol red-free medium was significantly stimulated by epidermal growth factor (EGF). This mitogenic effect of EGF was dose dependently antagonized by triptorelin, without affecting the concentrations of EGF receptors. Net tyrosine phosphorylation induced by 1 nM EGF was nearly completely suppressed by simultaneous addition of 10 mu M triptorelin or preincubation for 48 h with 100 nM triptorelin. This inhibitory effect of the LHRH agonist on EGF-induced net tyrosine phosphorylation was partly antagonized by exposure to 100 mu M sodium vandate, an inhibitor of phosphotyrosine phosphatase. In EFO-21, EFO-27, and HEC-1A cells exposure to 100 nM EGF for 5 min induced an approximately 5-fold increase in activity of mitogen activated protein kinase (MAP-kinase)/extracellular signal regulated kinase (ERK) which was virtually nullified, when the cells were exposed for 15 min to 10 mu M triptorelin. These data suggest that LHRH signal transduction mechanisms based on the activation of phospholipase C, protein kinase C, and adenylate cyclase, which operate in the pituitary gonadotroph, are not necessarily involved in the mediation of the antiproliferative effects of triptorelin in these ovarian and endometrial cancer cell lines. Instead our findings support the hypothesis that triptorelin interferes with mitogenic signal transduction, probably through antagonizing tyrosine kinase activity of the EGF receptor.     

Luteinizing hormone-releasing hormone as an autocrine growth factor in ES-2 ovarian cancer cell line

Agonistic and antagonistic analogs of luteinizing hormone-releasing hormone (LHRH) inhibit the growth of various cancers in vivo. This effect is mainly exerted through the suppression of the pituitary-gonadal axis and the creation of a state of sex steroid deprivation. In addition, much evidence has been accumulated in the past few years that LHRH analogs can also have direct effects on tumor growth mediated by specific LHRH receptors (-R) on tumor cells. Although an involvement of LHRH in the proliferation of some cancer cells has been postulated, it is still not clear at present whether LHRH produced locally has a stimulatory or inhibitory effect. In the present study we investigated whether LHRH can function as an autocrine growth factor in ovarian cancer. ES-2 human ovarian cancer cell line expresses mRNA for LHRH, which is apparently translated into peptide LHRH and then secreted by the cells, as demonstrated for the first time by the detection of LHRH-like immunoreactivity in conditioned media from the cells cultured in vitro. ES-2 cells also express mRNA for LHRH receptors. [D-Trp6]LHRH agonist at 10 ng/ml stimulates the proliferation of ES-2 in vitro after 48 h, but is inhibitory after 72 h and at concentrations of 1000 ng/ml. LHRH antagonist Cetrorelix inhibits growth of ES-2 cell line only at 1000 ng/ml. The incubation of ES-2 ovarian cancer cells in vitro with an LHRH antibody inhibited cell proliferation in a time and concentration-dependent manner. Collectively, our results suggest that LHRH may function as an autocrine growth factor in ovarian cancer.     

Racial disparity of epidermal growth factor receptor expression in prostate cancer.

PURPOSE: The epidermal growth factor receptor (EGFR) plays a critical role in prostate cancer (PC) signal transduction and is the target of a novel class of anticancer agents. Despite recent reports of interethnic variation in response to EGFR inhibitors, limited information exists regarding differences in expression of EGFR in PC patients. This has therapeutic relevance because a better understanding of the molecular basis underlying the ethnic variability will help in the design of individualized treatment regimens using EGFR inhibitors. PATIENTS AND METHODS: We investigated EGFR expression in a well-characterized cohort of PC patients to determine the association between EGFR expression and race. Tumor tissues from 202 radical prostatectomies performed between 1990 and 2000 at the Veterans Administration Medical Center (New York, NY) were studied (142 African Americans, 60 whites; median age, 67 years; stage T2, n = 130; stage > or = T3, n = 72; Gleason score < 7, n = 110; Gleason score > or = 7, n = 92). Membrane-specific EGFR expression was evaluated immunohistochemically. RESULTS: EGFR overexpression, defined as complete membrane staining in more than 10% of tumor cells, was observed in 75 of 202 patients (37%). There was a significant association between EGFR overexpression and African American race (P = .0006), higher pretreatment prostate-specific antigen (PSA; P = .02), and stage (P = .02), but not Gleason score (P = .33). The association between African American race and EGFR overexpression remained significant in a multivariate model after controlling for grade, stage, and pretreatment PSA simultaneously (P = .003). CONCLUSION: Our data demonstrate that race contributes significantly to variability of EGFR expression in prostate cancer. Racial background may have an impact on the design of clinical trials to test the efficacy of anti-EGFR agents.     

Endogenous secretion of epidermal growth factor peptides stimulates growth of DU145 prostate cancer cells

The growth rate of DU145 prostate cancer cells in vitro is slowed considerably by changing the growth medium every 24 h, suggesting dependence upon endogenously-secreted growth factors. Because previous studies have identified epidermal growth factor (EGF) in the conditioned medium from DU145 cells, [35S]labeled EGF was selectively immunoprecipitated from the culture medium at 24-h intervals for quantitation. Under the culture conditions used, there was an initial phase of slow growth, the EGF level secreted per cell was highest on day 3 after plating, and an increase in cell number was most evident between days 3 and 4. Finally, growth was assayed under culture conditions where the medium was replaced every 24 h with fresh medium in the absence or presence of 10 ng/ml added EGF. The EGF was able to increase the cell growth up to the levels seen in cultures where the medium was unchanged during the entire period. We interpret these results as evidence that endogenously secreted EGF-like growth factors participate in an autocrine growth stimulation of DU145 cells.     

Luteinising hormone-releasing hormone analogue reverses the cell adhesion profile of EGFR overexpressing DU-145 human prostate carcinoma subline

Cetrorelix, a luteinising hormone-releasing hormone (LHRH) analogue, has been shown to limit growth of the human androgen-independent prostate cell line DU-145, although other inhibitory actions may also be affected. Both growth and invasion of DU-145 cells are linked to autocrine epidermal growth factor receptor (EGFR) signalling. Invasiveness requires not only cells to migrate to conduits, but also reduced adhesiveness between tumour cells to enable separation from the tumour mass. Thus, we investigated whether Cetrorelix alters the DU-145 cell-cell adhesion and if this occurs via altered EGFR signalling. Pharmacologic levels of Cetrorelix limited the invasiveness of a highly invasive DU-145 subline overexpressing full-length EGFR (DU-145 WT). Extended exposure of the cells to Cetrorelix resulted in increased levels of the cell-cell adhesion complex molecules E-cadherin, alpha- and beta-catenin, and p120. Puromycin blocked the increases in E-cadherin and beta-catenin levels, suggesting that de novo protein synthesis is required. The Cetrorelix effect appears to occur via transmodulation of EGFR by a protein kinase C (PKC)-dependent mechanism, as there were no changes in DU-145 cells expressing EGFR engineered to negate the PKC transattenuation site (DU-145 A654); downregulation of EGFR signalling produced a similar upregulation in adhesion complex proteins, further suggesting a role for autocrine signalling. Cetrorelix increased the cell-cell adhesiveness of DU-145 WT cells to an extent similar to that seen when autocrine EGFR signalling is blocked; as expected, DU-145 A654 cell-cell adhesion also was unaffected by Cetrorelix. The increased adhesiveness is expected as the adhesion complex molecules moved to the cells' periphery. These data offer direct insight into the possible crosstalk pathways between the LHRH and EGFR receptor signalling. The ability of Cetrorelix to downregulate EGFR signalling and subsequently reverse the antiadhesiveness found in metastatic prostate cancer highlights a novel potential target for therapeutic strategies.     

cbl-b inhibits epidermal growth factor receptor signaling

The role of cbl-b in signaling by the epidermal growth factor receptor (EGFR) was studied and compared with c-cbl. We demonstrate in vivo, that cbl-b, like c-cbl, is phosphorylated and recruited to the EGFR upon EGF stimulation and both cbl proteins can bind to the Grb2 adaptor protein. To investigate the functional role of cbl proteins in EGFR signaling, we transfected cbl-b or c-cbl into 32D cells overexpressing the EGFR (32D/EGFR). This cell line is absolutely dependent on exogenous IL-3 or EGF for sustained growth. 32D/EGFR cells overexpressing cbl-b showed markedly inhibited growth in EGF compared to c-cbl transfectants and vector controls. This growth inhibition by cbl-b was the result of a dramatic increase in the number of cells undergoing apoptosis. Consistent with this finding, cbl-b overexpression markedly decreased the amplitude and duration of AKT activation upon EGF stimulation compared to either vector controls or c-cbl overexpressing cells. In addition, the duration of EGF mediated MAP kinase and Jun kinase activation in cells overexpressing cbl-b is shortened. These data demonstrate that cbl-b inhibits EGF-induced cell growth and that cbl-b and c-cbl have distinct roles in EGF mediated signaling.     

Luteinizing hormone-releasing hormone (LRH) agonist in the treatment of breast cancer, osteosarcoma and prostate carcinoma--analysis of 12 patients

This paper first reports the results of 12 patients with sex hormone-dependent neoplasms, including 9 women with breast cancer, 2 men with osteosarcoma and 1 man with prostate carcinoma, treated by LRH agonist, (D-Ala6, des-Gly-NH2(10))-LRH-ethylamide (LRH-A) 100-200 micrograms, IM, QD. After 15-30 days of administration, the concentrations of plasma mean estradiol, progesterone, testosterone, serum luteinizing hormone and follicle-stimulating hormone were lowered significantly in the peripheral blood of all patients, associating with improvement of the patients' general condition and reduction of the tumors and/or metastatic foci. No serious side effects were observed except vaginal irregular bleeding in isolated patients. Three patients died and the others were alive in follow-up of 4-30 months. The results suggest that LRH-A be useful in the treatment of the sex hormone-dependent tumors and worth further study.     

Concurrent chemoradiotherapy with low-dose docetaxel inhibits the growth of DU-145 prostate cancer xenografts

Introduction

Concurrent chemoradiotherapy (CCRT) has been widely used during the past decades in clinical trials and has now become a common treatment option in many clinical settings. The present study was designed to evaluate the efficacy of combining radiation with low-dose docetaxel in DU-145 prostate cancer xenograft models.

Methods

Male BALB/c nude mice bearing human DU-145 prostate tumors were assigned to four treatment groups: (1) control, (2) docetaxel (10 mg/kg/week, i.v., ×3 weeks), (3) radiation (2 Gy, q.d. ×5, ×3 weeks), (4) CCRT (the combination of docetaxel and radiation). Treatment efficacy was determined by tumor volume and tumor regression measurements. The extent of apoptosis in tumors in response to treatments was assessed via terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assay. In addition, immunohistochemical staining of CD34 was done to quantify microvessel density in the tumors.

Results

Our in vivo studies using DU-145 xenograft models in nude mice showed that CCRT compared to either alone significantly inhibited tumor growth, and the percentages of tumor regression were 32.6, 44.2, and 68.6 % for docetaxel, radiation, and CCRT, respectively. Moreover, CCRT did not significantly affected mice weight as compared to docetaxel or radiation alone. TUNEL assays showed that significantly more apoptotic cells were induced in the tumors treated with CCRT than either treatment alone. Anti-CD34 immunohistochemical staining indicated that CCRT significantly inhibited tumor angiogenesis.

Conclusion

These findings suggest that CCRT with low-dose docetaxel inhibits the growth of DU-145 prostate cancer xenografts, by enhancing apoptosis and suppressing angiogenesis. Based on these preclinical findings, we suggest that CCRT for the treatment of prostate cancer deserves further development.     

Role of fibroblast growth factor receptor signaling in prostate cancer cell survival.

BACKGROUND: Expression of fibroblast growth factors (FGFs) is increased in a substantial fraction of human prostate cancers in vivo and in prostate cancer cell lines. Altered FGF signaling can potentially have a variety of effects, including stimulating cell proliferation and inhibiting cell death. To determine the biologic significance of altered FGF signaling in human prostate cancer, we disrupted signaling by expression of a dominant-negative (DN) FGF receptor in prostate cancer cell lines. METHODS: PC-3, LNCaP, and DU145 prostate cancer cells were stably transfected with DN FGFR constructs, and LNCaP and DU145 cells were infected with a recombinant adenovirus expressing DN FGFR-1. The effect of DN FGFR-1 expression was assessed by colony-formation assays, cell proliferation assays, flow cytometry, and cytogenetic analysis. Key regulators involved in the G(2)-to-M cell cycle transition were assessed by western blotting to examine cyclin B1 expression and by in vitro kinase assay to assess cdc2 kinase activity. RESULTS: Stable transfection of the DN FGFR-1 construct inhibited colony formation by more than 99% in all three cell lines. Infection of LNCaP and DU145 prostate cancer cells with adenovirus expressing DN FGFR-1 led to extensive cell death within 48 hours. Flow cytometry and cytogenetic analysis revealed that the DN FGFR-1 receptor led to arrest in the G(2) phase of the cell cycle before cell death. Cyclin B1 accumulated in DN FGFR-1-infected LNCaP cells, but cdc2 kinase activity was decreased. CONCLUSIONS: These findings reveal an unexpected dependence of prostate cancer cells on FGF receptor signal transduction to traverse the G(2)/M checkpoint. The mechanism for the G(2) arrest is not clear. Our results raise the possibility that FGF-signaling antagonists might enhance the cell death induced by other prostate cancer therapies.     

Regulation of targeted chemotherapy with cytotoxic lutenizing hormone-releasing hormone analogue by epidermal growth factor

Targeting chemotherapy selectively to cancers can reduce the toxic side effects. AN-152, a conjugate of doxorubicin and [D-Lys6]-luteinizing hormone-releasing hormone (LH-RH), is more potent against LH-RH receptor-bearing cancers and produces less peripheral toxicity than doxorubicin. Many cancers, e.g., 50% of breast cancers, but few normal tissues express these receptors, providing a selective target for this cytotoxic conjugate. In this study, the effectiveness of AN-152 was heightened by receptor up-regulation. The cytotoxic effect of AN-152 can be regulated by the number of active LH-RH receptors on cancer cells. LH-RH receptor-positive (MCF-7) and -negative (UCI-107) cancer cells were treated with epidermal growth factor (EGF) or the somatostatin analogue, RC-160. EGF and RC-160 have been shown previously to regulate LH-RH receptors through phosphorylation. The effect of receptor regulation, by hormone exposure, on the cytotoxicity of AN-152 and doxorubicin and on the cellular uptake of AN-152, [D-Lys6]LH-RH, or doxorubicin was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and by two-photon laser scanning microscopy. The results demonstrated that the cellular entry of the conjugate was: (a) specific for cancers with LH-RH receptors; (b) up-regulated by EGF; (c) down-regulated by RC-160; and (d) the cytotoxicity of the AN-152 paralleled the efficiency of entry. This study illustrates the potential use of receptor regulation for increasing the efficacy of chemotherapeutic approaches that are directed to cell surface receptors.     

Luteolin inhibits insulin-like growth factor 1 receptor signaling in prostate cancer cells

Insulin-like growth factor 1 receptor (IGF-1R) activation is required for prostate cell proliferation. Prostate cancer is one of the most commonly diagnosed malignant tumors in Western countries. Overexpression of IGF-1R in prostate cancer is associated with tumor growth. These suggest that IGF-1R inhibitory agents may be of preventive and/or therapeutic value. With evidence accumulating for a chemopreventive role of flavonoids, the effects of luteolin, a bioactive flavonoid, on IGF-1R signaling in prostate cancer cells were examined. Luteolin inhibited insulin-like growth factor 1 (IGF-1) induced activation of IGF-1R and AKT in prostate cancer PC-3 and DU145 cells. Inhibition of AKT by luteolin resulted in decreased phosphorylation of its downstream targets, including p70S6K1, GSK-3beta and FKHR/FKHRL1. Luteolin also inhibited the IGF-1-induced activation of EGFR and MAPK/ERK signaling. Luteolin inhibited expression of cyclin D1 and increased expression of p21. As a result, luteolin suppressed proliferation and induced apoptosis of prostate cancer cells. Knockdown of IGF-1R by siRNA led to inhibition of proliferation of prostate cancer cells. Results of in vivo tumor growth assay indicated that luteolin inhibited PC-3 tumor growth. Immunoblotting of the extracts of tumor tissues showed that luteolin inhibited IGF-1R/AKT signaling. Our results provide a new insight into the mechanisms that luteolin is against cancer cells.     

The impact of gefitinib on epidermal growth factor receptor signaling pathways in cancer

The ErbB family of receptor tyrosine kinases, of which the epidermal growth factor receptor (EGFR) is the prototype, is associated with the formation and malignant progression of most of the common solid tumors. These molecules play a key role in a complex network of signal transduction pathways that function in normal development as well as in neoplastic transformation. The EGFR and other family members are therefore promising targets for new anticancer therapies. In normal tissues, EGFR-tyrosine kinase (TK) activity is strictly controlled. However, in tumor cells, there are multiple mechanisms that can lead to increased or inappropriate EGFR-TK activity, including altered expression of EGFR, its ligand, or interacting molecules; decreased deactivation through phosphatases or downregulation; or mutation of the EGFR protein. Novel therapeutic approaches aimed at inhibiting increased EGFR-TK activity include antibodies that block the extracellular ligand-binding site, antibody or ligand fusion proteins that specifically target toxins to the tumor cells, or small-molecule TK inhibitors (TKIs) that act intracellularly to block downstream signal transduction from EGFR. Studies have shown that such blockade can lead to reduced cellular proliferation, inhibition of survival signals, and inhibition of tumor metastasis and angiogenesis. Additionally, some agents, including EGFR antibodies and TKIs such as gefitinib have been demonstrated to be effective against various human solid tumors in preclinical models and have shown activity in advanced non-small-cell lung cancer and other solid tumors.     

Blockade of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling for therapy of metastatic human pancreatic cancer

We determined whether concurrent blockage of vascular endothelial growth factor (VEGF) receptor and epidermal growth factor (EGF) receptor signaling by two novel tyrosine kinase inhibitors, PTK 787 and PKI 166, respectively, can inhibit angiogenesis and, hence, the growth and metastasis of human pancreatic carcinoma in nude mice. Highly metastatic human pancreatic carcinoma L3.6pl cells were injected into the pancreas of nude mice. Seven days later, groups of mice began receiving oral doses of PTK 787 and PKI 166 three times weekly. Some groups of mice also received i.p. injections of gemcitabine twice a week. The mice were necropsied when the control mice became moribund. Treatment with PTK 787 and PKI 166, with gemcitabine alone, or with the combination of PTK 787, PKI 166, and gemcitabine produced 69, 50, and 97% reduction in the volume of pancreatic tumors, respectively. Administration of protein tyrosine kinase inhibitors and gemcitabine also significantly decreased the incidence of lymph node and liver metastasis. The therapeutic efficacy directly correlated with a decrease in circulating proangiogenic molecules (VEGF, interleukin-8), a decrease in microvessel density, a decrease in proliferating cell nuclear antigen staining, and an increase in apoptosis of tumor cells and endothelial cells. Therapies produced by combining gemcitabine with either PKI 166 or PTK 787 were similar to those produced by combining gemcitabine with both PKI 166 and PTK 787. These results suggest that blockade of either epidermal growth factor receptor or VEGF receptor signaling combined with chemotherapy provides an effective approach to the therapy of pancreatic cancer.     

Cytokine regulation by epidermal growth factor receptor inhibitors and epidermal growth factor receptor inhibitor associated skin toxicity in cancer patients

AimEpidermal growth factor receptor inhibitor (EGFRI) induced skin toxicity has a prognostic value suggesting skin toxicity can be a useful surrogate marker for successful epidermal growth factor receptor (EGFR) inhibition, improved response and survival. But the pathophysiology of EGFRI induced skin toxicity remains elusive. However the involvement of immunological mechanisms has been speculated. This study investigates the possible underlying mechanism of EGFR inhibition associated cytokine production in keratinocytes as well as in patients after treatment with epidermal growth factor receptor inhibitors (EGFRIs).MethodsNormal human epidermal keratinocytes (NHEK) were incubated for 2 and 24 h with different concentrations of EGFRI (erlotinib) for Western blot analysis and cytokine expression analysis, respectively. Inhibition of EGFR, extracellular-signal-regulated kinase 1/2 (Erk 1/2) and c-Jun was examined by Western blot analysis. Cytokine concentrations were measured by enzyme-linked immunosorbent assay (ELISA) in the NHEK cell supernatant and also in the serum of 186 cancer patients who are followed up for EGFRI induced skin rash.ResultsA significant inhibitory effect of EGFRI was seen on EGFR (Y845), Erk 1/2 and c-Jun in a dose dependent manner. Further downstream, increased CC-chemokine ligand 2 (CCL2), CC-chemokine ligand 5 (CCL5) and decreased interleukin-8 (IL-8) or CXCL8 expression was observed in keratinocytes. In EGFRI treated patients, low levels of serum CXCL8 corresponding to stronger EGFR inhibition were associated with a higher grade of skin toxicity (p = 0.0016) and a prolonged overall survival (p = 0.018).ConclusionsThe results obtained in this study indicate that EGFRI can regulate cytokines by modulating EGFR signalling pathway in keratinocytes. Moreover, serum levels of CXCL8 in EGFRI treated patients may be important for individual EGFRI induced skin toxicity and patient’s survival.     

Divergent responses to epidermal growth factor in hormone sensitive and insensitive human prostate cancer cell lines.

The present study was undertaken to compare the relationship between response to exogenous epidermal growth factor (EGF) and the expression of the EGF-receptor (EGF-R) in an androgen sensitive (LNCaP) and insensitive (DU145) prostate cancer cell line. Although both cell lines demonstrated a single EGF-R binding site of similar high affinities (mean dissociation constant (Kd) +/- S.D. for DU145 = 1.0 +/- 0.6 nmol l-1; LNCaP = 2.8 +/- 2.2 nmol l-1) the number of binding sites (RT) for the hormone insensitive DU145 cells (mean +/- S.D. = 2.5 +/- 1.0 x 10(5) sites/cell) and 10-fold greater than that expressed in the androgen responsive LNCaP cell line (mean +/- S.D. = 2.0 +/- 1 x 10(4) sites/cell). Additionally exogenous EGF only minimally affected the growth and DNA synthesis of DU145 cells whereas LNCaP cells showed a significant response which was dose dependent. The autologous production of EGF-like molecules by DU145 cells is believed to reduce the cells needs for exogenous mitogens, thereby rendering the cells autostimulatory. Treatment of LNCaP cells with Mibolerone--a synthetic androgen--did not affect either the expression of the EGF receptor or the proliferative response observed with EGF. Western blot analysis, using monoclonal antibodies directed against the EGF receptor revealed a band of approximately 170 kD with DU145 cell lysates but the LNCaP EGF receptor was not detected using this technique.     

Steroid receptor regulation of epidermal growth factor signaling through Src in breast and prostate cancer cells: steroid antagonist action

Under conditions of short-term hormone deprivation, epidermal growth factor (EGF) induces DNA synthesis, cytoskeletal changes, and Src activation in MCF-7 and LNCaP cells. These effects are drastically inhibited by pure estradiol or androgen antagonists, implicating a role of the steroid receptors in these findings. Interestingly, EGF triggers rapid association of Src with androgen receptor (AR) and estradiol receptor alpha (ERalpha) in MCF-7 cells or ERbeta in LNCaP cells. Here, we show that, through EGF receptor (EGFR) and erb-B2, EGF induces tyrosine phosphorylation of ER preassociated with AR, thereby triggering the assembly of ER/AR with Src and EGFR. Remarkably, experiments in Cos cells show that this complex stimulates EGF-triggered EGFR tyrosine phosphorylation. In turn, estradiol and androgen antagonists, through the Src-associated receptors, prevent Src activation by EGF and heavily reduce EGFR tyrosine phosphorylation and the subsequent multiple effects, including DNA synthesis and cytoskeletal changes in MCF-7 cells. In addition, knockdown of ERalpha or AR gene by small interfering RNA (siRNA) almost abolishes EGFR tyrosine phosphorylation and DNA synthesis in EGF-treated MCF-7 cells. The present findings reveal that steroid receptors have a key role in EGF signaling. EGFR tyrosine phosphorylation, depending on Src, is a part of this mechanism. Understanding of EGF-triggered growth and invasiveness of mammary and prostate cancer cells expressing steroid receptors is enhanced by this report, which reveals novel aspects of steroid receptor action.     

Targeting epidermal growth factor receptor signaling in the treatment of head and neck cancer

In this review, key aspects of epidermal growth factor receptor (EGFR) biology and the fruitful translation of these fundamental findings into recent treatment advances in head and neck squamous cell cancer (HNSCC) are highlighted. In contrast to a number of contemporary reviews of the EGFR, many of which focus on colorectal and nonsmall cell lung cancer, this review discusses the EGFR as a validated therapeutic target in HNSCC. Recent data confirm a survival advantage for the addition of the anti-EGFR monoclonal antibody cetuximab to definitive radiation therapy in locoregionally advanced HNSCC patients, as well as palliative benefits for patients with incurable recurrent and metastatic HNSCC. Small-molecule EGFR tyrosine kinase inhibitors also show considerable promise in this disease, both alone and in combination with radiation and chemotherapy. Both classes of anti-EGFR agent are generally well tolerated, with side effects (notably skin rash) that are distinct from the toxicities of conventional chemotherapy. Ongoing clinical trials will more clearly define the role for EGFR inhibitors in all treatment phases of HNSCC.     

Targeting epidermal growth factor receptor signaling in the treatment of head and neck cancer

In this review, key aspects of epidermal growth factor receptor (EGFR) biology and the fruitful translation of these fundamental findings into recent treatment advances in head and neck squamous cell cancer (HNSCC) are highlighted. In contrast to a number of contemporary reviews of the EGFR, many of which focus on colorectal and nonsmall cell lung cancer, this review discusses the EGFR as a validated therapeutic target in HNSCC. Recent data confirm a survival advantage for the addition of the anti-EGFR monoclonal antibody cetuximab to definitive radiation therapy in locoregionally advanced HNSCC patients, as well as palliative benefits for patients with incurable recurrent and metastatic HNSCC. Small-molecule EGFR tyrosine kinase inhibitors also show considerable promise in this disease, both alone and in combination with radiation and chemotherapy. Both classes of anti-EGFR agent are generally well tolerated, with side effects (notably skin rash) that are distinct from the toxicities of conventional chemotherapy. Ongoing clinical trials will more clearly define the role for EGFR inhibitors in all treatment phases of HNSCC.     

Transforming growth factor alpha and epidermal growth factor levels in bladder cancer and their relationship to epidermal growth factor receptor.

We have examined levels of epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha) in neoplastic and non-neoplastic bladder tissue using a standard radioimmunoassay technique. Tumour samples had much higher TGF-alpha levels compared with EGF and TGF-alpha levels in malignant tissue were significantly higher than in benign bladder samples. There was, in addition, a difference in mean EGF levels from ''normal'' bladder samples from non-tumour bearing areas of bladder in patients with bladder cancer compared with ''normal'' bladder tissue obtained at the time of organ retrieval surgery. Levels of EGF and TGF-alpha did not correlate with levels of EGF receptor (EGFR) as determined by a radioligand binding method but levels of TGF-alpha > 10 ng gm-1 of tumour tissue did correlate with EGFR positivity defined using immunohistochemistry. These data suggest that TGF-alpha is the likely ligand for EGFR in bladder tumours.