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10.1245/s10434-006-9123-8
Annals of Surgical Oncology 14:752-758 (2007)
© 2007 Society of Surgical Oncology
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Original Article

COX-2 Expression in Hepatocellular Carcinoma is an Initiation Event; While EGF Receptor Expression with Downstream Pathway Activation is a Prognostic Predictor of Survival

Jason Foster, MD1,2, Jennifer Black, PhD1, Charles LeVea, MD1, Thaer Khoury, MD1, Boris Kuvshinoff, MD1, Miland Javle, MD1 and John F. Gibbs, MD1,3

1 Department of Surgery, Roswell Park Cancer Institute, State University of New York at Buffalo, Elm & Carlton Streets, Buffalo, NY, USA
2 Department of Surgical Oncology, Creighton University Medical Center, Omaha, NE 68131, USA
3 Department of Gastrointestinal Surgery, Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263-0001, USA

Correspondence: Address correspondence and reprint requests to: John F. Gibbs, MD; E-mail: John.Gibbs{at}RoswellPark.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Introduction: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and is a leading cause of cancer mortality with over 90% of HCC patients succumbing to the disease. Current systemic therapies have had no measurable impact on survival in this disease; however there are small subsets of patients who benefit from systemic therapy who have been difficult to identify. Improvements in patient stratification and the development of biological therapies have resulted from the elucidation of the molecular mechanisms integral to tumor development and progression. Recent studies have found that COX-2 and EGFR are frequently inappropriately expressed in HCC compared to normal liver expression; however the presence of surface receptors does not always mean that the downstream pathway is active. In this study, we investigate the incidence and impact of activated EGFR downstream messengers phosphorylated akt (pakt) and/or phosphorylated MAPK (pMAPK) on survival in patients with HCC.

Method: Thirty consecutive HCC patients treated at a single institution were retrospectively reviewed. Patient data including age, sex, Child’s score, histological type, grade, stage, and survival were analyzed. Immunohistochemical staining was performed on formalin fixed, paraffin embedded tissues using monoclonal antibodies to COX-2, EGF receptor, pMAPK, and pakt. Histoscores were determined for each marker and evaluated for impact in survival, stage, and tumor grade.

Results: The median age was 67 years (39–83) and 67% of patients were male. Median survival was 9.8 months (1–47 months) for the whole group. COX-2 and EGFR expression was present in 90 and 67% of the tumors, respectively. Expression of activated downstream EGFR messengers was present in 53% of tumors (pMAPK 41%, pakt 31%). Median survival was significantly better in patients with downstream messenger expression, 24.4 months, compared to no expression, 4.7 months (P = 0.03). These groups were matched in age, stage, and Child’s score.

Conclusion: COX-2 and EGFR expression are commonly seen in HCC. Activated downstream EGFR expression is also common in HCC and is a predictor of improved survival. There may be a therapeutic role for EGFR tyrosine kinase inhibitors in this subset of patients and further investigation is warranted.

Key Words: Hepatocellular carcinoma • COX-2 • EGFR • Biological therapies


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hepatocellular carcinoma (HCC) is the fifth most common malignancy treated worldwide with approximately 564,000 new cases of HCC identified annually. The majority of these patients succumb to this disease within 8–10 months of diagnosis.1 The 5-year survival for patients with HCC is abysmal ranging from 5 to 8%.2,3 Only the small subset of patients who have resectable disease and the hepatic reserve to tolerate resection, truly have an opportunity of being cured of the disease. Even when an R0 resection can be accomplished, up to 70% of these patients will develop a local or distant hepatic recurrence after resection with the 5-year survival at best being 20–40%.4 Patients with small lesions (≤ 3 cm) who have the best prognosis still have a 20% risk of recurrent hepatic disease.5 Until more effective adjuvant systemic and local therapies are developed, improvements in outcomes will not occur.

Recently, data have been published characterizing the roles of the COX-2 and EGFR pathways in cancer formation. The COX-2 pathway has been found to induce autocrine effects that increase proliferation and inhibit apoptosis in cancer cells.6–9 Additionally, this pathway has been found to control the tumor microenvironment by promoting angiogenesis through the production of VEGF, as well as, activating metalloproteinases to enhance tumor invasiveness.9–12 Because COX-2 expression is present in 80–100% of tumors and the levels decrease with dedifferentiation; most groups have concluded that it is an initiating factor in HCC development.

The EGFR proteins family is a central pathway in many cell subtypes for normal growth and development. However, over-expression or dysregulation of EGF receptor leads to catastrophic autocrine cellular imbalance with increased proliferation and inhibition of apoptotsis.13 Perturbations in this family of proteins has been seen in many malignancies including gastrointestinal, head and neck, lung, ovarian, and breast cancers.14–18 EGF receptors activate a number of downstream pathways including PI3K/Akt, ras/MAPK and JAK/STAT signaling pathways. The PI3K/Akt pathway controls cellular survival through inhibition of apoptosis, while the ras/MAPK activation results in mitogenesis or cellular proliferation.13,19,20 Because of the high frequency of up-regulation of the EGF receptors in malignancy, it has become a prime target in the development of biological therapy.16

HCC tumors frequently express high levels of COX-2 and EGF receptors.21–23 The expression of these proteins has been associated with tumor biological behavior including differentiation, invasion, and angiogenesis.22,24,25 However, these groups have been unable to correlate EGFR expression with survival. With technical improvements in our ability to detect activated downstream substrates of cell surface receptors, we have found that not all cells that express the up stream receptors have activation of downstream targets that regulate the cellular events. Confirmation of pathway activation in tumor cells requires demonstration of the activation or expression of the downstream messengers.

In this study, we investigated the expression frequency of COX-2 and EGFR receptors in HCC tumors and hypothesized the following model. First, that COX-2 expression would be found in the majority of specimen, representing an early (initiation) event in tumor development. Secondly, that the activation of the EGFR pathway evident by the expression of phosphorylated MAPK (pMAPK) and/or akt (pakt) plays a role in tumor progression and is a predictor of survival.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Population
Thirty-two consecutive cases of HCC treated at Roswell Park Cancer Institute from January 1, 1990 to December 31, 2002 were reviewed. Thirty cases had adequate tissue and were included in the final analysis. A retrospective analysis of clinical data was done. Relevant data included age, gender, child’s score (A, B, C), histological grade, stage at presentation, treatment received and survival from the time of diagnosis. Institutional review board approval was obtained for this investigation.

Immunohistochemical Staining
Thirty-two consecutive cases of HCC were included for initial analysis and the diagnosis was established by examination of conventional hematoxylin and eosin stained slides. Thirty cases had adequate tissue material for immunohistochemical staining with COX-2 and EGF receptor. Twenty-nine cases had adequate tissue for pMAPK and pakt staining. For each case, a representative block containing adequate tumor cells was selected. Sections were cut at 5 µm, placed on charged slides and dried in a 60°C oven for 1 h. Upon return to room temperature, the slides were deparaffinized in three changes of Xylene and rehydrated using graded alcohols. Endogenous peroxidase was quenched with aqueous 3% H2O2 for 15 min and washed with phosphate buffered saline with 0.05% Tween-20 (PBS/T). Antibodies used, primary antibody concentration and incubation time, and antigen retrieval procedures are detailed in Table 1Go. After a PBS/T wash, 0.03% casein (in PBS/T) was used as a block for 30 min, then the primary antibody was applied to slides for 1 h, or overnight. A PBS/T wash was followed by the biotinylated secondary antibody (see Table 1Go for respective antibody) for 30 min. A PBS/T wash was followed by the streptavidin–peroxidase complex for 30 min. PBS/T was used as a wash and the chromogen DAB [DAKO, Carpinteria CA] was applied for 5 min. The slides were then counter-stained with hematoxylin, rinsed with water, dehydrated, cleared and cover slipped. Methodology for biomarkers were used in this study, their controls and interpretation of results has been described extensively by our group previously.26–29 A histoscore system was used for quantitation of results. Histoscores were assigned on the basis of multiplying the percentage of cells staining positive by the intensity of cytoplasmic staining. The gradation of staining depended on the intensity of staining (0 no staining, 1 weak, 2 moderate, and 3 strong staining) and the percentage of cells stained. The final score was calculated as the sum of each staining intensity multiplied by the percentage of corresponding area. For example: if a tumor shows 50% weak, 30% moderate and 20% strong staining, the score would be (50 x 1) + (30 x 2) + (20 x 3) = 170. Positive staining in this study was defined as a histoscore of 100 or greater, based on the criteria used by the reviewing pathologist (CL, TK).


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  		TABLE 1. List of antibodies and antigen retrieval techniques for immunostains
 
Histological Grading
The hepatocellular tumor specimens were also stained by routine H&E staining. The specimens were graded on the basis of the degree of tumor differentiation using the World Health Organization (WHO) grading system (World Health Organization: International Classification of Diseases for Oncology (ICD-O), 3rd edn. Geneva, Switzerland: WHO, 2000).

Statistical Analysis
The statistical analyses were performed in an exploratory manner on twenty-five patients who had all relevant clinical information and had adequate tissue for immunostaining. Kendall’s tau and Pearson correlation was employed to investigate the associations between biomarkers, and the significance of the associations was tested using the exact method. Survival figures of cases without expression (histoscores < 100) compared to those with expression (histoscores ≥100) for each biomarker were compared using the log-rank test and the Kaplan–Meier method. Survival figures by different levels of other diagnostic variables were also compared in a similar way. Multivariate relationship between patient survival and biomarkers along with other diagnostic parameters was investigated using the Cox proportional hazard model.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
Thirty patients were included in this study with a median age of 67 ranging from 39 to 83. There were 20 men and seven women. Three patients had no gender identification. Stage distribution was 5 I (17%), 7 II (23%), 8 III (27%), and 7 IV (23%). Three patients had no tumor stage available. Histologically, there were nine (30%) well, 13 (43%) moderate, and four (13%) poorly differentiated tumors; four tumors did not have final histology available. The Child’s score of the patients in this study were 18 (60%) Child A, 8 (20%) Child B, and 3 (10%) Child C, while three patients could not be scored. Fifteen patients (50%) underwent resection only; while another 5 (15%) had a resection followed by ablation, chemoembolization or chemotherapy. Four patients (13%) underwent chemoembolization alone. The six remaining patients received supportive care.

Immunohistochemical Staining and Outcomes
Table 2Go summarizes the expression of COX-2, EGFR, pMAPK, and pakt. The histoscore quantitation technique used in this study, described in the methods, has been previously published by our institution in cholangiocarcinoma carcinoma.30 Ninety % (27/30) of the HCC tumors had cytoplasmic expression of COX-2 (Fig. 1AGo), while 68% (20/30) expressed EGF receptor in the cytoplasm (Fig. 1BGo). Fifty-three percent (16/30) of the tumors had cytoplasmic expression of downstream messenger pakt (Fig. 1CGo) and/or pMAPK (Fig. 1DGo). The overall expression rates of pMAPK and pakt in our HCC population were 41% (12/29) and 31% (9/29), respectively. The inactive forms of these proteins were also present but these data are not shown.


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  		TABLE 2. Incidence of protein expression based on positive immunostaining
 

Figure 1
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  		FIG. 1. 100x histology of hepatocellular tumor sections illustrating positive cytoplasmic immunostaining for A COX-2, B EGF receptor, C activated MAPK (pMAPK), and D activated akt (pakt).

 
For the 25 patients who had all relevant information the median overall survival was 9.8 months with follow-up times ranging from 1 to 47 months. COX-2 expression was excluded from the multivariate analysis since only 2 of the 25 patients did not express COX-2, making any statistical comparison invalid. Therefore, multivariate analysis was performed looking at sex, age, T stage, expression of EGF receptor, and evidence of downstream EGF signal. The only variable found to correlate with survival was expression of activated EGFR downstream messengers, pMAPK and/or pakt (Tables 3Go, 4Go). The groups were matched in demographics, stage, and treatment modalities (Table 3Go). Median survival was significantly better for patients with EGF downstream signal, 24.4 months compared to no downstream signal, 4.7 months (P = 0.03).


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  		TABLE 3. Comparison of HCC tumors found to express downstream signals versus tumors that did not express signal
 

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  		TABLE 4. Multivariate analysis of factors impacting survival
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
HCC along with other primary hepatic malignancies is a disease that has a poor prognosis. Most patients present with advanced unresectable disease, while many with resectable disease have significant cirrhosis, lacking the hepatic reserve necessary to permit safe resection. Surgery remains to be the only curative modality, however this treatment is plagued with high intrahepatic recurrence rate since all current local, and systemic adjuvant modalities at best result in short-term regression, stabilizations, or symptomatic control. Clearly there is a need for the development of new therapies that may improve long-term survival.

In this study the COX-2 expression was present in 90% of the tumors. Sixty-five percent of tumors had cytosolic EGF receptor expression, with evidence of expression of downstream messengers pMAPK and pakt in 53% of these cases. Overall expression of pMAPK and pakt were 24 and 31%, respectively. This is the first study to show the co-expression of downstream messengers of the EGF receptors in hepatocellular tumor specimens. More importantly we found that presence of downstream messenger expression identified the subset of patients with an improved survival.

Many groups have found expression of COX-2 to be common in HCC with rates ranging from 70 to 97%.12,25,31,32 A study quantitating levels of COX-2 expression during injury and stages of tumor progression was done by Koga et al. They found that COX-2 levels increased with liver injury, peaked in well differentiated HCC tumors, and rapidly diminished in poorly differentiated tumors.22 Because increased levels of COX-2 expression occur early with liver injury and in well differentiated HCC tumors; COX-2 expression has been considered an early/initiation event in HCC tumor development. Like many other groups COX-2 was expressed in 90% of our HCC patients, providing additional evidence supporting its potential role in the initiation of HCC tumor development.

EGF receptor expression in HCC has been shown by many groups with reported expression rates of 25–67%.21,23,24 Our rate of expression was consistent with these studies. Other groups have linked the EGF receptor expression with differentiation, invasion and metastasis but have been unable to directly link it to survival.21,24,33–35 The impact on survival in these studies may have been missed because of the inclusion of patients who expressed EGFR receptors without confirmation of pathway activity or co-expression of downstream messengers. In our study we found that 30% (6/20) of patients who expressed EGF receptors did not have downstream activity. By looking at the pathway expression, the biological relevance of the pathway is captured; and in this study we look at two downstream messengers of the EGF pathway, activated MAPK and akt. The MAPK pathway has been found to be the pathway responsible for activation of proliferation and inhibition of differentiation; while the akt pathway is involved in anti-apoptotic activity.13,19,20,29,36–40 Receptor expression with co-expression of activated downstream messengers, makes this pathway a potential mediator of tumor cell survival and/or progression. However, since this was purely an investigation of protein expression, further studies testing the functional significance need to be done in both the basic science and clinical arenas.

The fact that the EGF pathway signaling subset had an improved survival was unexpected but not unprecedented. This has been reported in other studies, which have attributed the improved outcomes in this tumor population to responsiveness to antiproliferative therapy.41–43 Equally important is that this implies that the subset of tumors formed independent of the EGF pathway, biologically, have a more aggressive phenotype that appear to be refractory to our current treatment modalities. This represented 40% of our patients, including some who had EGF receptor expression that had no evidence of EGF pathway activation. Elucidating the molecular pathways involved in these tumors is essential to the development of treatment that may improve survival in this group.

The EGF pathway appears to be active in half our patients and predicts a survival benefit. Although, these patients experience a relative improvement in median survival, a median survival of 24 months is still poor, and the 5 year survival in these patients is still less that 10%. The treatment of these patients with EGF tyrosine kinase inhibitors may be of benefit in this subset of HCC tumors. Further studies investigating the frequency of pathway activity and tumor dependency on the pathway for viability and progression need to be performed. The inability to detect pre-malignant or early HCC, and the lack of effective systemic therapy, coupled with it global lethality, make this disease a worldwide problem. These tumors appear to be abundant in molecular targets susceptible to existing EGF and COX-2 biological therapies, and may facilitate the development of novel agents.


   FOOTNOTES
 
No part of this research has been published. There are no competing interests and no financial institutions or grants involved.

Received for publication May 25, 2006. Accepted for publication June 14, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Bosch FX, Ribes J, Diaz M, et al. Primary liver cancer: worldwide incidence and trends. Gastroenterology 2004; 127:5–16.[Medline]
  2. Seeff LB. Introduction: the burden of hepatocellular carcinoma. Gastroenterology 2004; 127:1–4.[CrossRef]
  3. El-Serag HB. Hepatocellular carcinoma: recent trends in the United States. Gastroenterology 2004; 127:27–34.[CrossRef][Medline]
  4. Chen MF, Hwang TL, Jeng LB, et al. Postoperative recurrence of hepatocellular carcinoma. Two hundred five consecutive patients who underwent hepatic resection in 15 years. Arch Surg 1994; 129:738–42.[Abstract/Free Full Text]
  5. Bismuth H, Majno PE, Adam R. Liver transplantation for hepatocellular carcinoma. Semin Liver Dis 1999; 19:311–22.[Medline]
  6. Liu CH, Chang SH, Narko K, et al. Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem 2001; 276:18563–9.[Abstract/Free Full Text]
  7. Cheng J, Imanishi H, Amuro Y, et al. NS-398, a selective cyclooxygenase 2 inhibitor, inhibited cell growth and induced cell cycle arrest in human hepatocellular carcinoma cell lines. Int J Cancer 2002; 99:755–61.[CrossRef][Medline]
  8. Nzeako UC, Guicciardi ME, Yoon JH, et al. COX-2 inhibits Fas-mediated apoptosis in cholangiocarcinoma cells. Hepatology 2002; 35:552–9.[CrossRef][Medline]
  9. Cervello M, Foderaa D, Florena AM, et al. Correlation between expression of cyclooxygenase-2 and the presence of inflammatory cells in human primary hepatocellular carcinoma: possible role in tumor promotion and angiogenesis. World J Gastroenterol 2005; 11:4638–43.[Medline]
  10. Cianchi F, Cortesini C, Bechi P, et al. Up-regulation of cyclooxygenase 2 gene expression correlates with tumor angiogenesis in human colorectal cancer. Gastroenterology 2001; 121:1339–47.[CrossRef][Medline]
  11. Jiang MC, Liao CF, Lee PH. Aspirin inhibits matrix metal-loproteinase-2 activity, increases E-cadherin production, and inhibits in vitro invasion of tumor cells. Biochem Biophys Res Commun 2001; 282:671–7.[CrossRef][Medline]
  12. Murono S, Yoshizaki T, Sato H, et al. Aspirin inhibits tumor cell invasiveness induced by Epstein-Barr virus latent membrane protein 1 through suppression of matrix metallopro-teinase-9 expression. Cancer Res 2000; 60:2555–61.[Abstract/Free Full Text]
  13. Liebmann C. Regulation of MAP kinase activity by peptide receptor signalling pathway: paradigms of multiplicity. Cell Signal 2001; 13:777–85.[CrossRef][Medline]
  14. Blank SV, Chang R, Muggia F. Epidermal growth factor receptor inhibitors for the treatment of epithelial ovarian cancer. Oncology (Huntingt) 2005; 19:553–9; discussion 560–2, 567.[Medline]
  15. Pomerantz RG, Grandis JR. The epidermal growth factor receptor signaling network in head and neck carcinogenesis and implications for targeted therapy. Semin Oncol 2004; 31:734–43.[CrossRef][Medline]
  16. Tedesco KL, Lockhart AC, Berlin JD. The epidermal growth factor receptor as a target for gastrointestinal cancer therapy. Curr Treat Options Oncol 2004; 5:393–403.[Medline]
  17. Tokunaga A, Onda M, Okuda T, et al. Clinical significance of epidermal growth factor (EGF), EGF receptor, and c-erbB-2 in human gastric cancer. Cancer 1995; 75:1418–25.[CrossRef][Medline]
  18. Zhou BP, Hung MC. Dysregulation of cellular signaling by HER2/neu in breast cancer. Semin Oncol 2003; 30:38–48.[Medline]
  19. Jackson JG, St Clair P, Sliwkowski MX, et al. Blockade of epidermal growth factor- or heregulin-dependent ErbB2 activation with the anti-ErbB2 monoclonal antibody 2C4 has divergent downstream signaling and growth effects. Cancer Res 2004; 64:2601–9.[Abstract/Free Full Text]
  20. Hamilton M, Wolfman A. Oncogenic Ha-Ras-dependent mitogen-activated protein kinase activity requires signaling through the epidermal growth factor receptor. J Biol Chem 1998; 273:28155–62.[Abstract/Free Full Text]
  21. Ito Y, Takeda T, Sakon M, et al. Expression and clinical significance of erb-B receptor family in hepatocellular carcinoma. Br J Cancer 2001; 84:1377–83.[CrossRef][Medline]
  22. Koga H, Sakisaka S, Ohishi M, et al. Expression of cyclooxygenase-2 in human hepatocellular carcinoma: relevance to tumor dedifferentiation. Hepatology 1999; 29:688–96.[CrossRef][Medline]
  23. Zhao YN, Cao J, Wu FX, et al. [Expression and significance of EGF mRNA and EGFR mRNA in hepatocellular carcinoma]. Ai Zheng 2004; 23:762–6.[Medline]
  24. Kira S, Nakanishi T, Suemori S, et al. Expression of transforming growth factor alpha and epidermal growth factor receptor in human hepatocellular carcinoma. Liver 1997; 17:177–82.[Medline]
  25. Qiu DK, Ma X, Peng YS, et al. Significance of cyclooxygenase-2 expression in human primary hepatocellular carcinoma. World J Gastroenterol 2002; 8:815–7.[Medline]
  26. Malik SN, Siu LL, Rowinsky EK, et al. Pharmacodynamic evaluation of the epidermal growth factor receptor inhibitor OSI-774 in human epidermis of cancer patients. Clin Cancer Res 2003; 9:2478–86.[Abstract/Free Full Text]
  27. Malik SN, Bedolla RG, Hidalgo M, et al. Immunohistochemical determination of EGFR-tyrosine kinase inhibition in clinical samples. Methods Mol Med 2003; 85:135–40.[Medline]
  28. Malik SN, Brattain M, Ghosh PM, et al. Immunohistochemical demonstration of phospho-Akt in high Gleason grade prostate cancer. Clin Cancer Res 2002; 8:1168–71.[Abstract/Free Full Text]
  29. Jiang D, Yang H, Willson JK, et al. Autocrine transforming growth factor alpha provides a growth advantage to malignant cells by facilitating re-entry into the cell cycle from suboptimal growth states. J Biol Chem 1998; 273:31471–9.[Abstract/Free Full Text]
  30. Javle MM, Tan D, Yu J, et al. Nuclear surviving expression predicts poor outcome in cholangiocarcinoma. Hepatogastroenterology 2004; 51:1653–7.[Medline]
  31. Murono S, Inoue H, Tanabe T, et al. Induction of cyclooxy-genase-2 by Epstein-Barr virus latent membrane protein 1 is involved in vascular endothelial growth factor production in nasopharyngeal carcinoma cells. Proc Natl Acad Sci USA 2001; 98:6905–10.[Abstract/Free Full Text]
  32. Shiota G, Okubo M, Noumi T, et al. Cyclooxygenase-2 expression in hepatocellular carcinoma. Hepatogastroenterology 1999; 46:407–12.[Medline]
  33. Sipeki S, Bander E, Buday L, et al. Phosphatidylinositol 3-kinase contributes to Erk1/Erk2 MAP kinase activation associated with hepatocyte growth factor-induced cell scattering. Cell Signal 1999; 11:885–90.[CrossRef][Medline]
  34. Liu F, Qi HL, Chen HL. Regulation of differentiation- and proliferation-inducers on Lewis antigens, alpha-fucosyltransferase and metastatic potential in hepatocarcinoma cells. Br J Cancer 2001; 84:1556–63.[CrossRef][Medline]
  35. Wang Q, Lin ZY, Feng XL. Alterations in metastatic properties of hepatocellular carcinoma cell following H-ras oncogene transfection. World J Gastroenterol 2001; 7:335–9.[Medline]
  36. Tang P, Steck PA, Yung WK. The autocrine loop of TGF-alpha/EGFR and brain tumors. J Neurooncol 1997; 35:303–14.[CrossRef][Medline]
  37. Hambek M, Baghi M, Strebhardt K, et al. STAT 3 activation in head and neck squamous cell carcinomas is controlled by the EGFR. Anticancer Res 2004; 24:3881–6.[Abstract/Free Full Text]
  38. Gibson SB. Epidermal growth factor and trail interactions in epithelial-derived cells. Vitam Horm 2004; 67:207–27.[Medline]
  39. Yokoi K, Kim SJ, Thaker P, et al. Induction of apoptosis in tumor-associated endothelial cells and therapy of orthotopic human pancreatic carcinoma in nude mice. Neoplasia 2005; 7:696–704.[CrossRef][Medline]
  40. Mukohara T, Engelman JA, Hanna NH, et al. Differential effects of gefitinib and cetuximab on non-small-cell lung cancers bearing epidermal growth factor receptor mutations. J Natl Cancer Inst 2005; 97:1185–94.[Abstract/Free Full Text]
  41. Lee CM, Lee RJ, Hammond E, et al. Expression of HER2neu (c-erbB-2) and epidermal growth factor receptor in cervical cancer: prognostic correlation with clinical characteristics, and comparison of manual and automated imaging analysis. Gynecol Oncol 2004; 93:209–14.[CrossRef][Medline]
  42. Chakravarti A, Winter K, Wu CL, et al. Expression of the epidermal growth factor receptor and Her-2 are predictors of favorable outcome and reduced complete response rates, respectively, in patients with muscle-invading bladder cancers treated by concurrent radiation and cisplatin-based chemotherapy: a report from the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 2005; 62:309–17.[CrossRef][Medline]
  43. Altundag O, Altundag K, Morandi P, et al. Association between epidermal growth factor receptor mutation and improved survival in never-smokers with primary adenocarcinoma of the lung. Chest 2005; 127:2292.



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