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Expression of Hepatoma-Derived Growth Factor Is a Strong Prognostic Predictor for Patients With Early-Stage Non–Small-Cell Lung Cancer

From the Department of Thoracic/Head and Neck Medical Oncology, Departments of Biostatistics, Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Department of Pediatrics, The Johns Hopkins University, School of Medicine, Baltimore, MD

Address reprint requests to Li Mao, MD, Department of Thoracic/Head and Neck Medical Oncology, Unit 432, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: lmao{at}mdanderson.org

	ABSTRACT

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PURPOSE: Hepatoma-derived growth factor (HDGF), which is unrelated to hepatocyte growth factor, can stimulate DNA synthesis and cell proliferation on entering the nucleus. We hypothesize that HDGF plays an important role in biologic behavior of early-stage non–small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Ninety-eight patients with pathologic stage I NSCLC who underwent curative surgery were studied. Immunohistochemistry was used to determine the expression level of HDGF in the tumor specimens. The intensity of the protein staining and percentage of stained tumor cells were used to determine a labeling index. Statistical analyses, all two-sided, were performed to determine the prognostic effect of HDGF expression levels on clinical parameters and outcomes.

RESULTS: The mean ± standard deviation HDGF labeling index in the 98 tumors was 185 ± 41. Patients whose tumors had higher HDGF indexes ( 185) had a significantly poorer probability of overall survival at 5 years after surgery than did those with lower HDGF indexes (0.26 v 0.82; P < .0001). Similarly, the 5-year disease-specific and disease-free survival probabilities were lower in those with higher HDGF indexes (0.42 v 0.92, and 0.34 v 0.71; P < .0001 and P = .0008; respectively). Multivariate analysis indicated that HDGF level was an independent predictor of overall, disease-specific, and disease-free survivals.

CONCLUSION: Overexpression of HDGF is common in early-stage NSCLC. The expression level in tumor cells is strongly correlated with poor overall, disease-specific, and disease-free survivals, suggesting HDGF may be a powerful prognostic marker for patients with early-stage NSCLC.

	INTRODUCTION

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Lung cancer is the most common cause of cancer-related death in the United States, accounting for more deaths than those caused by prostate, breast, and colorectal cancers combined.¹ The prognosis for patients with lung cancer is correlated with disease stage at the time of diagnosis. Patients with stage I non–small-cell lung cancer (NSCLC), the earliest stage in current staging system, have a 5-year survival rate of approximately 60%, whereas patients with stage II to IV disease have 5-year survival rates ranging from 40% to less than 5%.^2,3 Unfortunately, even among patients with stage I NSCLC, 40% will die of the disease within 5 years after potentially curative surgery. Recent studies have shown that patients with early stage NSCLC may benefit from adjuvant chemotherapy following curative surgical attempt.^4,5 These findings may lead the adjuvant chemotherapy to become standard care for those patients. However, only 4% of the patients may actually benefit from such therapy, while most of the patients will suffer undesired and potentially fatal side effects.⁵ Therefore, the identification of novel strategies to further stratify such patients based on their likelihood to benefit from an adjuvant therapy is an unmet need.

Hepatoma-derived growth factor (HDGF), which is unrelated to hepatocyte growth factor, is a heparin-binding growth factor originally purified from media conditioned with the human hepatoma cell line HuH-7, and can stimulate proliferation of Swiss 3T3 cells.⁶ The amino acid sequence, as deduced from a cDNA clone of HDGF, contains 240 residues with a motif homologous to the consensus sequences of bipartite nuclear localization sequence and a DNA-binding PWWP motif (Fig 1A). The precise function of HDGF is unknown. Recent studies indicate that HDGF is highly expressed during early development of many tissues, including cardiovascular,⁷ kidney,⁸ and liver⁹ tissues. Although lacking the typical secretory sequence present in most secretory proteins,¹⁰ HDGF has been shown to act as a potent exogenous mitogen for HuH-7,¹¹ COS-7,¹¹ aortic vascular smooth muscle cells,¹² and endothelia cells.⁸

View larger version (23K): [in this window] [in a new window]   Fig 1. (A) Putative domains of hepatoma-derived growth factor (HDGF). (B) HDGF expression in non–small-cell lung cancer (NSCLC) cell lines and paired normal lung tissue specimens and primary NSCLC specimens, as well as (C) normal lung tissue specimens from patients without primary lung cancer (patients with metastatic lung tumors). Actin is used as a loading control. N, normal lung tissue specimens; T, primary NSCLC specimens.

	PATIENTS AND METHODS

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Study Population
Patients were included in the study if they were diagnosed with pathologic stage I NSCLC; had undergone lobectomy or pneumonectomy for complete resection of their primary tumors at The University of Texas M.D. Anderson Cancer Center (Houston, TX) from 1975 through 1990; had not received adjuvant chemotherapy or radiation therapy before or after surgery; had at least 5 years of follow-up data; and had adequate paraffin-embedded tissue sections available in the institution's tumor archive. During the period between 1975 and 1990, a total of 588 patients were diagnosed as having pathologic stage I NSCLC and treated surgically at M.D. Anderson. Tissue sections were available for 105 of these 588 patients, and sections from 98 patients contained adequate tumor cells for evaluation. The follow-up information was based on chart review and from reports from the M.D. Anderson tumor registry service. The study was reviewed and approved by the institution's Surveillance Committee to allow us to study the tissues and pertinent follow-up information. Tissue sections were from each tissue block, stained with hematoxylin-eosin, and reviewed to confirm the diagnosis and the presence or absence of tumor cells. NSCLC cell lines (H157, H226, H292, H358, H460, H522, A549, H596, H1299, H1792, H1944, Calu-1, and SK-Mes-1) used in the study were obtained from American type Culture Collection (Manassas, VA) and were grown in RPMI-1640 median with 10% fetal bovine serum (Life Technologies Inc, Rockville, MD).

Immunohistochemical Analysis
Tissue sections (4 µm thick) from formalin-fixed and paraffin-embedded tissue blocks were mounted on positively charged glass slides. Slides were baked at 60°C for 1 hour and then deparaffinized through a series of xylene baths. Rehydration was performed with graded concentrations of alcohol. To retrieve antigenicity, tissue sections were treated with microwaves in 10 mmol/L citrate buffer (pH 6.0) for 10 minutes. The sections were then immersed in methanol containing 0.3% hydrogen peroxidase for 20 minutes to block the endogenous peroxidase activity, and incubated in 2.5% blocking serum for 30 minutes to reduce nonspecific binding. Sections were incubated overnight at 4°C with an affinity-purified rabbit polyclonal antibody produced against the COOH-terminal amino acids (222-237) of the mouse HDGF sequence at a dilution of 1:4000 rabbit anti-HDGF polyclonal antibody,¹² followed by incubation for 30 minutes with biotinylated antirabbit immunoglobulin G (Vector Laboratories, Burlingame, CA). The sections were then processed using standard avidin-biotin immunohistochemistry according to the manufacturer's recommendations. Diaminobenzidine was used as a chromogen, and commercial hematoxylin was used for counterstaining.

The HDGF labeling index was defined as the weighted mean of percentage of tumor cells displaying nuclear immunoreactivity (calculated by counting the number of HDGF positive tumor cells among at least 1,000 tumor cells for each tissue section manually) multiplied by the degree of the staining intensity (1, 2, or 3, defined as weak staining, moderate staining, or strong staining, respectively). The final index of each tumor was the average of indices generated by two observers (H.R. and X.T.). The differences between the two observers were less than 20% in almost all cases. The weak staining in the smooth muscle cells of blood vessels was used as an internal control and the basis for the intensity score. Almost all tumor cells showed some degree of staining.

Western Blot Analysis
Tissues or cells were either homogenized or harvested in lysis buffer 50 mmol/L HEPES, 1% Triton X-100, 10 mmol/L NaF, 30 mmol/L Na3P04, 150 mmol/L NaCl, and 1 mmol/L EDTA and freshly added 10 mmol/L glycerophosphate, 1 mmol/L Na3VO4, 20 µg/mL pepstatin A, 10 µg/mL aprotinin, 20 µg/mL leupeptin, and 40 µmol/L microcystin-LR. Twenty micrograms of total proteins from each sample was separated in sodium dodecyl sulfate-polyacrylamide gel electrophoresis using a Bio-Rad Mini-Protean II apparatus (Schleicher & Schuell BioScience, Keene, NH), and separated proteins in the gels were transfered to nitrocellulose membrane. The membranes were then blocked with 5% nonfat milk for 2 hours at room temperature followed by incubation with the rabbit anti-HDGF antibody (1:10,000 dilution) at 4° C overnight. The immune reactive band was detected using a goat-antirabbit immunoglobulin G horseradish peroxidase conjugate (1:10,000; Jackson ImmunoResearch Lab, West Grove, PA,) as the secondary antibody and SuperSignal West Pico Substrate (Pierce Biotechnology, Rockford, IL) as the detection agent. A mouse antiactin monoclonal antibody AC-15 (Sigma, St. Louis, MO) was used to normalize protein loading.

Statistical Analysis
Survival probability as a function of time was computed by the Kaplan-Meier estimator. The variance of the Kaplan-Meier estimator was computed by the Greenwood formula. The 5-year survival probabilities were estimated and compared by the asymptotic z between the high expression and low expression groups. The log-rank test was used to compare patients' survival time between groups. Overall, disease-specific (ie, those who died of lung cancer-related causes specifically), and disease-free (ie, those who developed recurrence and/or metastasis) survivals were analyzed. HDGF-labeling index was analyzed as a continuous variable as well as a categoric variable. The mean labeling index and quartiles of the labeling index were used as cutoff points for HDGF in the survival analysis. The ² test was used to test equal proportion between groups in two-way contingency tables. Cox regression was used to model the risks of HDGF expression level on survival time, with adjustment for clinical and histopathologic parameters (age, sex, race, smoking status, and histologic subgroup). Martingale residual analysis was used to determine the functional form for HDGF (untransformed data on the continuous scale) to best explain its effect on survival through a Cox regression model. The Martingale residual plots using the Martingale residuals, from a Cox model that includes only baseline hazard function but no covariate, on the vertical axis and HDGF on the horizontal axis were provided. By applying a nonparametric smoother to create a line, the plots allow one to examine visually the nature of the relationship between the residuals and the HDGF scores. Appropriate transformation and/or cutoff points can be chosen accordingly. All statistical tests are two-sided and a P value of .05 or lower was considered statistically significant.

	RESULTS

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Of the 98 patients included in this study, 71 patients died, and 27 patients were still alive at the time of last follow-up. Among the 71 patients who died, 29 died of lung cancer, and 42 died of other causes including heart diseases, respiratory diseases, and other organ failures. The median follow-up time was 10.1 years among the patients who remained alive. Patient ages at the time of diagnosis ranged from 37 to 82 years, with a median age of 62.5 years; this is similar to the age distribution in a large database of NSCLC at M.D. Anderson (data not shown). Twenty-four (24%) of the patients were women, and 74 (76%) were men, which is comparable to the sex distribution of the disease in the 1970s and 1980s.² Ninety-six percent of the patients were smokers or former smokers. The histology types of squamous, adenocarcinoma, and others were found in 40%, 45%, and 15% of the patients, respectively. The 5-year overall survival rate was 55%, and the 5-year disease-specific survival rate was 71% in our patient population; these rates are similar to the rates reported in a previous study with a large number of cases from our institution.¹³ The general clinical characteristics of the patients are shown in Table 1.

We analyzed the expression status of HDGF protein in the 98 primary tumor samples from patients with pathologic stage I NSCLC by immunohistochemistry using a polyclonal anti-HDGF antibody. HDGF staining was observed in all tumor sections but at various intensities (Fig 2). Strong nuclear staining with minimal cytoplasmic staining was observed in many lung adenocarcinomas (Fig 2A through C). The staining intensity was in general weaker and more variable in squamous cell type (Fig 2D and E). The mean labeling index was 185¹⁴ in the overall tumor population with range from 100 to 291. The quartiles of the HDGF labeling index were 158, 182.5, and 211, respectively (25th, 50th, and 75th percentiles). Thirty-four percent of the adenocarcinomas exhibited an HDGF labeling index more than 211 (highest quartile) while only 15% of the squamous cell carcinomas did so; however, this difference was not statistically significant (P = .09). Weak cytoplasmic staining was observed in some HDGF-positive squamous carcinoma cells. In normal lung tissues, vascular smooth muscle cells might show weak staining and were used as an internal control (intensity level 1). In normal lung tissues, the HDGF expression level was low (Fig 2F). The HDGF expression level was not associated with age, sex, or race. In 40 tumors, HDGF expression and the expression of the proliferation marker Ki-67¹⁴ were compared. We failed to observe an association between the two markers (Spearman's correlation coefficient = 0.1; P = .52).

View larger version (90K): [in this window] [in a new window]   Fig 2. Hepatoma-derived growth factor expression detected by immunohistochemistry in lung adenocarcinomas (A, B, and C), lung squamous cell carcinomas (D and E) and bronchial epithelium in adjacent normal lung tissue (F).

View larger version (35K): [in this window] [in a new window]   Fig 3. Probability of (A, D) overall survival; (B, E) cancer-specific survival; and (C, F) disease-free survival by levels of hepatoma-derived growth factor (HDGF) expression in primary non–small-cell lung cancer (NSCLC). The Kaplan-Meier method was used to determine the survival probability, and the log-rank test was used to compare the survival curves between groups.

To determine whether HDGF expression level is an independent factor in predicting survival probability for patients with pathologic stage I NSCLC, we performed multicovariable analysis using the Cox model. We found that HDGF expression level was the only independent predictor of disease-specific and disease-free survival probabilities (P < .0001) among the parameters tested, including age, sex, race, smoking status, and tumor histology. When overall survival was analyzed, HDGF expression level remained the most significant independent predictor (P < .0001); not surprisingly, age was also an independent predictor for overall survival (P = .0002). Martingale residual analysis showed that the Cox model fit the data well. It was confirmed that there was a linear relationship of higher HDGF and poorer overall, disease-specific, and disease-free survivals, suggesting that the higher the HDGF expression, the worse the clinical outcome observed in early stage NSCLC patients (Fig 4).

View larger version (16K): [in this window] [in a new window]   Fig 4. Martingale residual analysis shown as scatter plots of null Martingale residuals versus hepatoma-derived growth factor expressions. A linear trend was revealed in each subpanel by fitting the nonparametric, lowess-smoothing regression lines through the data points. (A) overall survival; (B) cancer-specific survival; and (C) disease-free survival.

	DISCUSSION

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The finding that the expression level of HDGF in NSCLC strongly correlates with patients' clinical outcomes suggests that HDGF plays an important role in lung tumorigenesis and in the determination of the biologic behavior of NSCLC. The analysis of HDGF labeling index by quartiles indicated a dose-dependent relationship between HDGF expression and survivals (Figs 3D through F). The striking differences between the patients in the lowest quartile and those in the highest quartile are consistent with the fact that the scoring method used for immunohistochemistry is more objective for cells expressing a very high level of proteins or a very low level of proteins while more subjective for cells expressing a medium level of proteins. A linear relationship between the HDGF expression level and patients' clinical outcome was further confirmed by using Martingale residual analysis (Fig 4). In the multivariate analysis, HDGF expression was an independent predictor of overall, disease-specific, and disease-free survivals. The consistency of the results from different statistical analyses may allow us to conclude that HDGF has an important role in determining the behavior of NSCLC and is a promising biomarker for classifying patients with early-stage NSCLC. Given the advances in adjuvant therapy,⁵ it must now be considered to offer adjuvant chemotherapy to patients whose primary tumors have been surgically resected in a curative attempt because 4% of these patients may benefit from such additional treatment. If it becomes standard care, however, most of the patients will suffer unwanted toxicity, which can be fatal to some patients, without gaining benefit in survival and quality of life. Therefore, the identification of patients with the highest risk of dying of lung cancer after potentially curative surgical treatment is a critical step in selecting patients for subsequent treatment with adjuvant therapy.

Although this study was not designed to provide direct evidence demonstrating that HDGF promotes tumorigenesis or facilitates metastasis, our findings together with data from previous reports provide a strong rationale to suggest such possibilities. In an in vitro study, Kishima et al¹⁹ showed that downregulation of HDGF by antisense oligonucleotides can inhibit proliferation of hepatoma cell lines. Besides being mitogenic, HDGF has been shown to play a role in renal vascular development and in vascular lesion formation.⁸ Mori et al²⁰ recently reported that HDGF can stimulate proliferation of lung epithelial cells in both in vitro and in vivo models. Therefore, HDGF may promote proliferation of tumor cells, as well as serve as a paracrine factor to facilitate neovascular formation, which is important for invasion and metastasis. Interestingly, we did not observe a correlation between HDGF and Ki-67 expression in the present study, suggesting that HDGF contributes to the aggressive biologic behavior through its paracrine activity rather than by stimulating tumor cell proliferation. We have, in fact, noticed that tumor cells at the invading front and metastases in lymph nodes exhibited stronger HDGF staining compared with the noninvading cells and the primary tumor sites (Tang and Mao, unpublished data). Interestingly, there were nine patients who developed brain metastasis after surgery in this study population. Eight of the nine patients were in the high HDGF group. The only patient whose primary tumor had a low HDGF labeling index developed brain metastasis 6 months after surgery but survived for more than 6 years (data not shown).

In summary, our data demonstrated that HDGF expression is quantitatively associated with poor prognosis in all three types of clinical outcomes (disease-free survival, disease-specific survival, and overall survival) and strongly suggests that HDGF is involved in the disease aggressiveness, progression, and lethality. HDGF is a promising prognostic marker, not only to identify individuals with poor prognostic potential for more aggressive treatment, but also point to a new direction for searching effective molecular targeted therapies.

Note: The anti-HDGF antibody used in this study and/or monoclonal antibodies we are developing currently will be made available upon request.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Supported in part by Department of Defense Grant DAMD17-01-1-0689-1; and National Cancer Institute Grants PO1 CA91844, UO1 CA86390, and P30 CA 16620.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
1. Parkin DM, Pisani P, Ferlay J: Global cancer statistics. CA Cancer J Clin 49:33-64, 1999[Abstract/Free Full Text]

2. Jemal A, Thomas A, Murray T, et al: Cancer statistics, 2002. CA Cancer J Clin 52:23-47, 2002[Abstract/Free Full Text]

3. Willians DE, Pariolero PC, Davis CS, et al: Survival of patients surgically treated for stage I lung cancer. J Thorac Cardiovasc Surg 82:70-76, 1981[Abstract]

4. Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 311:899-909, 1995[Abstract/Free Full Text]

5. Le Chevalier T, for the IALT Investigators: Results of the randomized international adjuvant lung cancer trial (IALT): Cisplatin-based chemotherapy (CT) vs no CT in 1,867 patients with resected non–small-cell lung cancer. Proc Am Soc Clin Oncol 22:2, 2003 (abstr 6)

6. Nakamura H, Kambe H, Egawa T, et al: Partial purification and characterization of human hepatoma-derived growth factor. Clin Chim Acta 183:273-284, 1989[CrossRef][Medline]

7. Everett AD: Identification, cloning, and developmental expression of hepatoma-derived growth factor in the developing rat heart. Dev Dyn 222:450-458, 2001[CrossRef][Medline]

8. Oliver JA, Al-Awqati Q: An endothelial growth factor involved in rat renal development. J Clin Invest 102:1208-1219, 1998[Medline]

9. Enomoto H, Yoshida K, Kishima Y, et al: Hepatoma-derived growth factor is highly expressed in developing liver and promotes fetal hepatocyte proliferation. Hepatology 36:1519-1527, 2002[CrossRef][Medline]

10. von Heijne G: A new method for predicting signal sequence cleavage sites. Nucleic Acids Res 14:4683-4690, 1986[Abstract/Free Full Text]

11. Nakamura H, Izumoto Y, Kambe H, et al: Molecular cloning of complementary DNA for a novel human hepatoma-derived growth factor. Its homology with high mobility group-1 protein. J Biol Chem 269:25143-25149, 1994[Abstract/Free Full Text]

12. Everett AD, Lobe DR, Matsumura ME, et al: Hepatoma-derived growth factor stimulates smooth muscle cell growth and is expressed in vascular development. J Clin Invest 105:567-575, 2000[Medline]

13. Mountain CF: Value of the new TNM system staging system for lung cancer. Chest 96:47S-49S, 1989[Free Full Text]

14. Soria JC, Jang SJ, Khuri FR, et al: Overexpression of cyclin B1 in early-stage non–small-cell lung cancer and its clinical implication. Cancer Res 60:4000-4004, 2000[Abstract/Free Full Text]

15. Everett AD, Stoops T, McNamara CA: Nuclear targeting is required for hepatoma-derived growth factor-stimulated mitogenesis in vascular smooth muscle cells. J Biol Chem 276:37564-37568, 2001[Abstract/Free Full Text]

16. Stec I, Nagl SB, van Ommen GJ, et al: The PWWP domain: A potential protein–protein interaction domain in nuclear proteins influencing differentiation? FEBS Lett 473:1-5, 2000[CrossRef][Medline]

17. Qiu C, Sawada K, Zhang X, et al: The PWWP domain of mammalian DNA methyltransferase Dnmt3b defines a new family of DNA-binding folds. Nat Struct Biol 9:217-224, 2002[Medline]

18. Kishima Y, Yamamoto H, Izumoto Y, et al: Hepatoma-derived growth factor stimulates cell growth after translocation to the nucleus by nuclear localization signals. J Biol Chem 277:10315-10322, 2002[Abstract/Free Full Text]

19. Kishima Y, Yoshida K, Enomoto H, et al: Antisense oligonucleotides of hepatoma-derived growth factor (HDGF) suppress the proliferation of hepatoma cells. Hepatogastroenterology 49:1639-1644, 2002[Medline]

20. Mori M, Morishita H, Nakamura H, et al: Hepatoma-derived growth factor is involved in lung remodeling by stimulating epithelial growth. Am J Respir Cell Mol Biol 30:459-469, 2004[Abstract/Free Full Text]

Submitted February 10, 2004; accepted May 20, 2004.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ren, H. Articles by Mao, L. Search for Related Content PubMed PubMed Citation Articles by Ren, H. Articles by Mao, L.