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Clinical Cancer Research Vol. 6, 790-797, March 2000
© 2000 American Association for Cancer Research

Advances in Brief

Differential Expression of E-cadherin and Type IV Collagenase Genes Predicts Outcome in Patients with Stage I Non-Small Cell Lung Carcinoma1

Roy S. Herbst, Seiji Yano, Hiroki Kuniyasu, Fadlo R. Khuri, Corazon D. Bucana, Fang Guo, Diane Liu, Bonnie Kemp, J. Jack Lee, Waun Ki Hong and Isaiah J. Fidler2

Departments of Thoracic/Head and Neck Medical Oncology [R. S. H., F. K., F. G., D. L., B. K., W. K. H.], Cancer Biology [S. Y., H. K., C. D. B., I. J. F.], and Biostatistics [J. J. L.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Because routine histopathological examination of primary non-small cell lung cancer does not predict disease outcome, we correlated disease outcome with the expression level of multiple genes that regulate distinct steps of the metastatic process in 60 formalin-fixed, paraffin-embedded, archival specimens of stage I lung carcinoma from patients undergoing curative surgery at the M. D. Anderson Cancer Center. The expression of E-cadherin (related to cell cohesion), type IV collagenase [matrix metalloproteinase (MMP)-2 and MMP-9, related to invasion], and three angiogenic molecules, basic fibroblast growth factor, vascular endothelial growth factor/vascular permeability factor, and interleukin 8, were examined by a colorimetric in situ mRNA hybridization technique. The expression levels of the individual genes analyzed by a Cox univariate analysis were not prognostic. In contrast, the ratio between expression of type IV collagenases (mean of the expression of MMP-2 and MMP-9) and E-cadherin, the MMP:E-cadherin ratio (measured at the periphery of each tumor), was significantly higher in patients with recurrent disease than in patients who remained disease free (P = 0.00003). Longer overall survival and reduced disease recurrence rates were significantly associated with a lower MMP:E-cadherin ratio (<2) by a Kaplan-Meier survival analysis (P = 0.0002 and P = 0.0001, respectively). Multiple covariate analyses of overall and disease-free survival also concluded that the MMP:E-cadherin ratio was a significant prognostic factor when corrected for age (P = 0.0001). Determination of this gene expression ratio in individual human lung cancers might therefore be used to direct tailored treatment for individual patients with resectable lung cancer.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
Lung cancer accounts for 175,000 deaths annually in the United States, and most attributable to NSCLC3 are caused by metastasis. The prognosis for lung cancer is best in patients with stage I disease; however, even in these patients, >40% will relapse subsequent to surgical resection (1, 2, 3, 4) . Because detailed histopathological examination of primary lesions cannot be used to accurately predict disease outcome, there exists a great need to identify molecular markers with which to distinguish patients with resectable lung cancer at risk of recurrent disease.

Several molecular prognostic factors for human lung cancers have been proposed, including the presence of K-ras (5) , the loss of blood group antigen A (6) , and elevated bcl-2 expression (7) . None of these factors, however, have been accepted for routine clinical use. Two univariate and multivariate analyses of multiple prognostic indicators identified pathological stage, histological subtype, and tumor invasiveness (into lymph nodes and blood vessels) as critical prognostic factors (8 , 9) . The presence of K-ras, the absence of p21-ras, and low levels of bcl-2 protein, shown to be important negative factors, also correlated with disease outcome (9) . In addition, a recent multivariate analysis of 260 patients with surgically resected stage I/II lung cancer demonstrated shorter survival for patients with overexpression of bcl-2 antigen and Ki67 (10) . In this study, tumor microvessel density did not show statistical significance (10) . In other studies, however, the extent of vascular supply to lung cancers as measured by microvessel density has been shown to correlate directly with disease stage and inversely with survival (11, 12, 13, 14) .

Because most patients with resectable lung cancer succumb to metastatic disease (1, 2, 3, 4) , prognostic factors based on the metastatic potential of these neoplasms should predict disease outcome. The process of tumor metastasis is highly selective and consists of multiple, sequential events that include growth, induction of angiogenesis, detachment, invasion, adhesion, and proliferation (15) . This is followed by the induction of angiogenesis at distant sites (15, 16, 17) . Because each of the discrete steps of metastasis is regulated by independent genes, the identification of cells with metastatic potential in heterogeneous neoplasms requires multiparametric, multivariate analysis of relevant gene expression (15 , 18 , 19) . Our laboratory has developed a rapid, colorimetric, ISH technique to detect the expression of specific genes that regulate the different steps of metastasis (including angiogenesis; Refs. 18 , 20, and 21 ). This ISH technique uses oligonucleotide probes to detect specific mRNA transcripts in frozen and formalin-fixed, paraffin-embedded specimens and can determine the expression level of multiple genes that regulate different steps of metastasis such as E-cadherin (which is related to cell cohesion/detachment), collagenase type IV (MMP-2 and MMP-9, which is related to invasion), and bFGF, VEGF/VPF, and IL-8 (which are related to angiogenesis). Previous reports from our laboratory demonstrate that the analysis using these genes (but not others) predicts metastatic potential of individual patients’ colorectal carcinoma (21, 22, 23) , gastric carcinoma (24) , prostate carcinoma (25) , and pancreatic carcinoma (26) . On the basis of these findings, we hypothesized that this panel of genes could be used effectively to analyze NSCLC. The current report concerns 30 cases of stage I lung adenocarcinoma and 30 cases of stage I lung squamous cell carcinoma from the archives of the M. D. Anderson Cancer Center. Our analysis of the expression of metastasis-related genes and the ratio between the relative expression levels lead us to conclude that this assay can indeed be used to assess prognosis and ultimately direct specific treatment for this deadly disease.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
NSCLC Patients.
Archival specimens of 33 adenocarcinoma cases and 30 squamous carcinoma cases were identified by a pathologist without regard to clinical outcome data. Upon examination of the histopathology and clinical data, three adenocarcinoma cases were found to represent stage IIIA disease (positive mediastinal lymph nodes). These three cases were eliminated from the final analysis, which dealt with 30 adenocarcinomas and 30 squamous cell carcinomas. The patient characteristics are listed in Table 1Citation . Patient survival was verified and updated through the Tumor Registry as of July 1, 1998. By the last follow-up, 33 patients had died and 27 patients were alive.


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  		Table 1 Patient characteristics

 
Oligonucleotide Probes.
Specific antisense oligonucleotide DNA probes for seven different metastasis-related genes were designed complementary to the mRNA transcripts, based on published reports of the cDNA sequences (18 , 27, 28, 29, 30, 31, 32, 33, 34, 35) . The specificity of the oligonucleotide sequences was initially determined by a GenBank/European Molecular Biology Laboratory database search, using the Genetics Computer Group sequence analysis program (Genetics Computer Group, Madison, WI) and based on the FastA algorithm that showed 100% homology with the target gene and minimal homology with nonspecific mammalian gene sequences (36) . The specificity of each sequence was also confirmed by Northern blot analysis (26) . A poly d(T)20 oligonucleotide was used to verify the integrity of mRNA in each sample (21, 22, 23) . All DNA probes were synthesized with six biotin molecules (hyperbiotinylated) at the 3' end via direct coupling using standard phosphormidine chemistry (Research Genetics, Huntsville, AL; Refs. 35 and 37 ). The lyophilized probes were reconstituted to a 1-µg/µl stock solution in 10 mM Tris-HCl (pH 7.6) and 1 mM EDTA. The stock solution was diluted with probe diluent (Research Genetics) immediately before use. The working dilutions of each probe are shown in Table 2Citation .


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  		Table 2 Sequence of oligonucleotide probes

 
ISH.
Tissues stained with H&E were first reviewed for the presence of tumor cells. ISH was performed as described previously using the Microprobe manual staining system (Fisher Scientific, Pittsburgh, PA; Ref. 26 ). Tissue sections (4 µm thick) of formalin-fixed, paraffin-embedded specimens were mounted on silane-coated ProbeOn slides (Fisher Scientific). The slides were placed in a Microprobe slide holder, dewaxed, and dehydrated with Autodewaxer and Autoalcohol (Research Genetics), followed by enzymatic digestion with pepsin (35) . Hybridization of the probe was carried out for 60 min at 45°C, and the samples were then washed three times with 2x SSC for 2 min at 45°C (1x SSC = 0.15 M NaCl, 0.015 M sodium citrate). The samples were incubated for 30 min in alkaline phosphatase-labeled avidin at 45°C, briefly rinsed in 50 mM Tris buffer (pH 7.6), rinsed for 1 min with alkaline phosphatase enhancer (Biomeda Corp., Foster City, CA), and incubated for 30 min with the chromogen substrate FastRed (Research Genetics) at 45°C. A positive reaction in this assay stained red. Control for endogenous alkaline phosphatase included treatment of the samples in the absence of the biotinylated probe and use of chromogen in the absence of any oligonucleotide probes. To check the specificity of the hybridization signal, the following controls were used: (a) RNase pretreatment of tissue sections; (b) a biotin-labeled sense probe; and (c) a competition assay with unlabeled antisense probe. A markedly decreased or absent signal was obtained with these treatments.

Image Analysis to Quantify Intensity of Color Reaction.
Stained sections were examined in a Zeiss photomicroscope (Carl Zeiss, Inc., Thornwood, NY) equipped with a three-chip charge-coupled device color camera (model DXC-960 MD; Sony Corp., Tokyo, Japan). The images were analyzed using Optimas image analysis software (version 5.2; Bothell, WA). The slides were prescreened by one of the investigators to determine the range in staining intensity of the slides to be analyzed. Images covering the range of staining intensities were captured electronically, a color bar (montage) was created, and a threshold value was set in the red, green, and blue modes of the color camera. All subsequent images were quantified based on this threshold. The integrated absorbance of the selected fields was determined based on its equivalence to the mean log inverse gray scale value multiplied by the area of the field. The samples were not counterstained; therefore, the absorbance was attributable solely to the product of the ISH reaction. For each section, we determined the absorbance in several 2 x 2-mm zones located at the periphery of the tumors or at the foci of stromal invasion. Three to five different fields in each 2 x 2-mm zone were quantified to derive an average value by a reader who was kept blinded from the clinical outcome. The intensity of staining was standardized to that of the integrated absorbance of poly d(T)20 and determined by comparison with the integrated absorbance of nonpathological lung epithelium (tumor-free tissue), which was set at 100.

MMP:E-cadherin Ratio.
The MMP:E-cadherin ratio was calculated as the ratio of the expression of MMP (an average value of MMP-2 + MMP-9) divided by the expression level of E-cadherin. This ratio has been shown previously to correlate with prognosis in prostate (25) , pancreas (26) , colon (21, 22, 23) , and gastric cancers (24) .

Statistical Analysis.
The minimum level of gene expression among the groups was compared by the Wilcoxon rank sum test. Survival probability was estimated by the Kaplan-Meier method (38) . The prognostic effect of putative covariates on disease-free survival and overall survival was examined by the univariate and stepwise multiple-covariate Cox models.


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Expression of Metastasis-related Genes in Stage I NSCLC Specimens.
Prior to analysis, the integrity of mRNA in each sample was verified by using a poly d(T)20 probe (22 , 39) . All 60 samples had an intense histochemical reaction, indicating that the mRNA was well preserved. After ISH with the different probes, a quantitative value for each probe was determined by comparing the expression at the most intensely stained tumor area with that of normal, tumor-free lung tissue. In normal bronchial tissue, cytoplasmic staining of the metastasis-related genes was observed in bronchial epithelial cells, bronchial glands, type I and IV alveolar cells, and macrophages. The quantitative data are summarized in Table 3Citation . The expression of all of the genes under study except E-cadherin was reproducibly higher in the tumor tissue than in tumor-free tissue. No significant differences in gene expression were found between the adenocarcinoma and squamous cell carcinoma groups. In general, the expression of the genes analyzed as a single factor did not correlate with overall survival or disease-free survival (Table 4)Citation .


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  		Table 3 Expression of metastasis-related genes in stage I human NSCLC

 

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  		Table 4 Cox model: univariate and multiple-covariate analyses

 
The Ratio Between Expression of MMP-2, MMP-9, and E-cadherin Predicts Disease Recurrence.
The expression of MMP-9 and MMP-2 was compared with the expression of E-cadherin. The calculated ratio between these values differed between the adenocarcinomas (2.20 ± 1.1) and the squamous carcinomas (1.55 ± 0.38). Two representative cases for stage I adenocarcinomas are shown in Fig. 1Citation , and two representative cases for stage I squamous cell carcinomas are shown in Fig. 2Citation . Staining with H&E and probing with the poly d(T) oligonucleotide provide evidence for histological type and RNA integrity, respectively. Fig. 1ACitation exhibits a case of an adenocarcinoma with a low (1.0) MMP:E-cadherin ratio, and Fig. 1BCitation shows an adenocarcinoma with a high (3.9) MMP:E-cadherin ratio. Fig. 2ACitation shows a case of a stage I squamous cell carcinoma with a low (1.2) MMP:E-cadherin ratio, whereas Fig. 2BCitation exhibits a case of stage I squamous cell carcinoma with a high (2.9) MMP:E-cadherin ratio. As a whole, tumor tissue had reduced E-cadherin expression (76 ± 34) and increased MMP expression (MMP-2, 124 ± 50.2; MMP-9, 127 ± 52.6) as compared with adjacent normal tissue (Table 3)Citation . No significant differences were observed in the mean ratios when compared for substage (T1 versus T2), sex, and age.



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  		Fig. 1. ISH analysis for expression of E-cadherin, MMP-2, and MMP-9 in human lung adenocarcinomas and in tumor-free tissue. H&E staining shows the tumors to be moderately differentiated adenocarcinomas. Hybridization with a hyperbiotinylated poly d(T)20 probe confirmed the integrity of mRNA (red reaction). The expression intensity for E-cadherin and MMP-2 and MMP-9 in the tumor-free tissue was assigned a value of 100, and the measurements in the tumor tissue are relative to that number. The MMP:E-cadherin ratio defined as [(MMP-2 + MMP-9) ÷ 2] ÷ E-cadherin was 1.0 (A) and 3.9 (B). Bar, 50 µm.

 


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  		Fig. 2. ISH analysis of E-cadherin, MMP-2, and MMP-9 mRNA in human lung squamous cell carcinomas and in tumor-free tissue. H&E staining confirms the tumor to be a squamous cell carcinoma. Hybridization with hyperbiotinylated poly d(T)20 probe confirmed the integrity of mRNA (red reaction). The expression intensity for E-cadherin and MMP-2 and MMP-9 in tumor-free tissue was assigned a value of 100. The ratio of [(MMP-2 + MMP-9) ÷ 2] ÷ E-cadherin was 1.3 (A) and 2.9 (B). Bar, 50 µm.

 
A higher MMP:E-cadherin ratio was significantly associated with shorter overall survival (P = 0.002) and shorter disease-free survival (P = 0.00003; Table 4Citation ). Furthermore, using a stepwise multiple-covariate Cox model analysis, both the MMP:E-cadherin ratio and age were chosen. After adjustment for age, the MMP:E-cadherin ratio was a highly significant predictor of decreased overall survival (P = 0.0001). Similar results were found for disease-free survival, where the MMP:E-cadherin ratio is the only significant prognostic factor.

Kaplan-Meier survival curves are shown in Fig. 3Citation . Using a cutoff value for the MMP:E-cadherin ratio of 2.0 (corresponding to the third quartile of the ratio), there was a significant difference in overall survival (median, 10.2 versus 2.3 years; P = 0.0002) and disease-free survival (median, not reached versus 1.2 years; P = 0.0001), favoring the group with a ratio <2.0 (Fig. 3, A and B,Citation respectively). This also held true when the 30 adenocarcinoma cases were evaluated independently; however, the squamous carcinoma cell subgroup analyzed alone did not achieve statistical significance.



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  		Fig. 3. Kaplan-Meier survival curves versus MMP:E-cadherin expression ratio in resected stage I NSCLCs. The overall survival differed significantly between tumors with a MMP:E-cadherin ratio of <2.0 and those with a ratio higher than or equal to 2.0 (A; P = 0.0002). Significant differences (P = 0.0001) in disease-free survival are shown in B.

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
We determined whether the expression level of metastasis-related genes in stage I human lung cancer would have prognostic significance. Age, substage (T1 and T2), histology, and sex, as well as levels of expression of bFGF, VEGF/VPF, and IL-8, did not predict overall patient survival or disease recurrence. However, the ratio between the expression of MMP-2, MMP-9, and E-cadherin significantly correlated with disease-free and overall patient survival.

We have reported previously that the metastatic potential of human colon (21, 22, 23) , gastric (24 , 40) , prostate (25) , and pancreatic (26) cancers can be identified by a multiparametric analysis for the expression of genes that encode for epidermal growth factor receptor (growth), bFGF, IL-8 (angiogenesis), E-cadherin (cell cohesion), and MMP-2 and MMP-9 (invasion). Like other neoplasms, human lung cancers consist of multiple cell types, including tumor cells, fibroblasts, normal epithelial cells, endothelial cells, and infiltrating leukocytes (15) . Because metastasis can be produced by a small subpopulation of tumor cells (<1.0% of the tumor), detecting the expression of metastasis-related genes requires a sensitive technique (15 , 41) . We chose ISH because it identifies the cellular source of the mRNA as well as intratumoral heterogeneity in expression, whereas Northern blot analysis represents only the average levels of mRNA of all of the cells in a sample (21 , 22) .

As was the case for other human carcinomas, the ratio between expression of E-cadherin and collagenase type IV was a highly significant predictor of survival. Importantly, in each disease, the ratio cutoff between groups differed, as would be expected from tissues with a different biological phenotype. In lung cancer, we found the ratio of 2.0 to separate between two distinct prognostic groups. Specifically, the MMP:E-cadherin ratio of 2 corresponded to the third quartile of the ratio. Significant results (at P < 0.01) of the predictive value of the MMP:E-cadherin ratio were consistently found for overall survival using all cutpoints >=1.8 and for disease-free survival using all cutpoints >=1.7. The corrected Ps remained statistically significant after applying the method proposed by Altman et al. (42) to correct for the choice of optimal cutpoint using {epsilon} of 5 and 10%.

The observed results are consistent with the biological roles that E-cadherin and collagenase type IV play in the metastatic cascade. E-cadherin is a cell surface glycoprotein involved in calcium-dependent homotypic cell-to-cell cohesion (43) . It is localized at the epithelial junction complex and is responsible for the organization, maintenance, and morphogenesis of epithelial tissues. Reduced levels of E-cadherin are associated with a decrease in cellular/tissue differentiation and increased histological grade in different epithelial neoplasms (44, 45, 46) . Transfection of E-cadherin-encoding cDNA into invasive cancer cells has been shown to inhibit their invasiveness (47) .

Once cells detach from the primary tumor, they must invade the host stroma if they are to metastasize (48 , 49) . Degradation of blood vessel basement components, especially type IV collagen, is one of the necessary steps in metastasis. The levels of Mr 72,000 and Mr 92,000 type IV collagenase in human and rodent neoplasms directly correlate with invasion and metastasis, and specific inhibitors of MMPs have been shown to inhibit tumor cell invasion (48, 49, 50, 51, 52) . Thus, a decrease in the expression of E-cadherin and increase in collagenase type IV activity would enhance detachment of tumor cells and invasion.

In this limited series, the disease-free survival of patients with T1 did not differ from those with T2 disease. Although it is encouraging that the MMP:E-cadherin ratio also did not differ between these groups, only a larger series can determine the true significance of the analysis.

It is interesting that in our study, the expression of the proangiogenic molecules (bFGF, VEGF/VPF, and IL-8) did not correlate with survival (12 , 52 , 53) . The regulation of these genes might be at the posttranscriptional level, necessitating analysis by immunohistochemistry, which we did not do. Alternatively, their expression could be more critical in more advanced disease presentations.

The validation of these data requires a prospective study or analysis of an independent set of NSCLC patients. Other potential markers of prognosis in this population, including those involved in neoplastic angiogenesis, should also be useful in identifying individuals most likely to benefit from adjuvant therapies. At present, there are several MMP inhibitors available in clinical practice, and one could conceive of a clinical trial where these agents are given to patients manifesting a high MMP:E-cadherin ratio at the time of their resection.

In summary, we used the ISH technique to examine the concurrent expression of metastasis-related genes in formalin-fixed, paraffin-embedded specimens of resected stage I lung carcinomas from patients undergoing curative surgery. Using quantification of gene expression by colorimetric scanning and standardization to nonpathological lung tissue, we conclude that the ratio of MMP-2 and MMP-9 expression to E-cadherin expression at the periphery of lung cancers can accurately and significantly predict outcome (P = 0.00003) in individual patients with early stage disease.


   ACKNOWLEDGMENTS
 
We thank Walter Pagel for critical review and comments and Lola López and Bich Tran for expert assistance in the preparation of the manuscript.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported in part by Cancer Center Support Core Grants CA16672 and R35-CA42107 from the National Cancer Institute, NIH (to I. J. F.), and grants from the M. D. Anderson Physician Referral Service, the University of Texas Specialized Program of Research Excellence in Lung Cancer Development Award, and an American Society of Clinical Oncology Career Development Award (to R. S. H.). Back

2 To whom requests for reprints should be addressed, at Department of Cancer Biology, Box 173, The University of Texas M. D. Anderson Cancer Center; 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 792-8577; Fax: (713) 792-8747; E-mail: ifidler{at}mdanderson.org Back

3 The abbreviations used are: NSCLC, non-small cell lung cancer; ISH, in situ hybridization; MMP, matrix metalloproteinase; bFGF, basic fibroblast growth factor; VEGF/VPF, vascular endothelial growth factor/vascular permeability factor; IL, interleukin; IHC, immunohistochemistry. Back

Received 10/28/99; revised 12/28/99; accepted 1/11/00.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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