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Clinical Cancer Research Vol. 5, 1093-1097, May 1999
© 1999 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Endothelial Cell Nitric Oxide Synthase in Peritumoral Microvessels Is a Favorable Prognostic Indicator in Premenopausal Breast Cancer Patients1

Kirsten Mortensen, Susanne Holck, Ib Jarle Christensen, Jan Skouv, David M. Hougaard, Jens Blom and Lars-Inge Larsson2

Department of Molecular Cell Biology, Statens Serum Institut, Copenhagen [K. M., D. M. H., J. B., L-I. L.]; Institute of Anatomy and Physiology, The Royal Veterinary and Agricultural University, DK-1870 Frederiksberg C [K. M., L-I. L.]; Department of Pathology, Hillerød Hospital, DK-3400 Hillerød [S. H.]; Finsen Laboratory, Rigshospitalet, DK-2100 Copenhagen [I. J. C.]; and Exiqon, DK-2950 Vedbæk [J. S.], Denmark


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Nitric oxide (NO) is involved in tumor cell apoptosis and has additional effects on tumor blood flow, immune responses, and angiogenesis. We, therefore, studied endothelial cell NO synthase (ecNOS) protein expression in a retrospective series of 118 patients with primary invasive breast cancer. Immunocytochemically stained paraffin sections were used for determining the frequency of (a) tumor cells, (b) intratumoral microvessels, and (c) peritumoral microvessels that were positive for ecNOS. A high density of ecNOS positive microvessels in the normal tissue surrounding the tumor (measured by the variable PEMVD) was associated with significantly better recurrence-free and overall survival. The prognostic significance was observed in a representative series of premenopausal patients and was independent of other factors, including lymph node status. The counting procedure was highly reproducible and correlated to stereological measurements but was influenced by heterogeneity of the tissue samples. Analyzing two sections per patient improved the discriminative power by reducing the influence of tissue heterogeneity and produced highly significant results (recurrence-free survival, P < 0.001; overall survival, P < 0.0001). Immunoreactive ecNOS in microvessels is an independent prognostic factor in breast cancer and may reflect a mechanism of endothelial defense against invasion by tumor cells. Individual variations in ecNOS may be related to environmental, hormonal, and genetic factors and could represent a therapeutic target.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Endothelial cells interact with tumor cells during tumor vascularization and during the metastatic process (1 , 2) . Tumor cells produce factors like vascular endothelial growth factor that influence endothelial functions, whereas endothelial cells produce adhesion molecules and soluble molecules that interact with tumor cells. Endothelial cell production of NO3 has attracted great interest with respect to its roles in both regulating blood flow and angiogenesis and killing tumor cells and reducing tumor cell adhesion to endothelium (3, 4, 5, 6, 7, 8) . Generation of large amounts of NO can directly kill tumor cells by cytotoxic actions. In addition, NO is involved in programmed cell death (apoptosis). Interestingly, NO can both induce (9, 10, 11, 12) and protect against apoptosis (13, 14, 15) . In endothelial cells, NO protects against apoptosis induced by tumor necrosis factor-{alpha} (15) , whereas cytokine-activated endothelial NO production can kill adjacent tumor cells (5 , 8) . Two forms of NOSs occur in endothelial cells: inducible NOS and ecNOS. The latter enzyme is Ca2+ dependent, and its expression is regulated by shear stress, transforming growth factor-ß, and estrogen (16, 17, 18) . Very recently, we have shown that ecNOS is expressed in and regulates apoptosis in cultured human breast cancer cells.4 Against this background, we decided to examine human breast cancers for ecNOS expression and its potential prognostic importance. Our results show that, in premenopausal patients, high ecNOS expression in endothelial cells in normal tissue surrounding the tumor is associated with significantly longer recurrence-free and overall survival.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Immunocytochemistry and Quantitation.
The material comprised 118 primary invasive breast cancers randomly selected from files at the Pathology Department, Hillerød Hospital, between 1978 and 1983. Tumors had been fixed in 10% buffered formalin and embedded in paraffin. Five-µm sections were treated with methanol-H202, microwaved, and stained with a monoclonal ecNOS antibody without cross-reactivity to the neuronal or inducible forms (neuronal NOS and inducible NOS; Transduction Laboratories, Lexington, KY) at 1.6 µg/ml or with a type-matched (control) digoxigenin monoclonal antibody (Boehringer Mannheim, Mannheim, Germany) at 3.2 µg/ml using a streptavidin-peroxidase bridge method (19) . Coded sections were used for counting immunopositive endothelial cell profiles at x200 magnification (20 , 21) in a 0.19838-mm2 large microscopic field. All immunocytochemically stained endothelial cells that occurred separately were counted. The entire area of the tumor and the surrounding normal tissue were analyzed separately. Results were expressed as averages of the six fields containing the highest ecNOS-positive microvessel densities (EMVD) in the tumoral (TEMVD) and peritumoral (PEMVD) areas, respectively. Immunopositive tumor cells were point-counted using an ocular grid. Hits over positive and negative tumor cells were recorded in six random fields and expressed as the mean ± SD of the percentage positive cells.

Patient Data.
Patient data were obtained from the DBCG (22) after approval by the local ethical committee and included age at operation, lymph node status, tumor diameter, grade of anaplasia, ER and PgR status, treatment protocol, and presence of relapse (Table 1)Citation . Patients were monitored for recurrence for 10 years. The median follow-up time exceeded 10 years. Typing and grading were performed using the grading system of Elston and Ellis (23) as a guideline. The material comprised 83 invasive ductal, 18 lobular, 13 medullary, and 4 miscellaneous carcinomas. Menopausal status was not available, so age of <55 or >=55 years was used. Fifty-six % of the patients were <55 years of age, and the clinical characteristics of these patients closely matched those of premenopausal patients in the DBCG database (1977–1982; Table 2Citation ). In contrast, the clinical characteristics of the older patients deviated from those of the patients in the DBCG database.


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  		Table 1 Clinical characteristics of the patients (n = 118)

 

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  		Table 2 Clinical characteristics of patients in the DBCG database from 1977 to 1982 (n = 10,025)

 
Statistics.
Comparison of characteristics between groups was done using the {chi}2 test for homogeneity. Ps below 5% were considered significant. Correlations were calculated using the Spearman rank correlation coefficient. Life table analysis of recurrence-free survival and overall survival was performed using the Kaplan-Meier product limit method. Tests for equality over strata were performed using the log-rank test. Multivariate analysis was done using the Cox proportional hazards model. The assumption of proportionality was validated graphically. Actual values of covariates were entered (continuous), or the values were dichotomized by the median. Traditional covariates that have been included are age, the number of malignant lymph nodes, grade of anaplasia, tumor size, ER and PgR status, and grading. The data on ER and PgR were incomplete (see Table 1Citation ) and were only used for correlation to TEMVD and PEMVD.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Immunocytochemistry demonstrated specific ecNOS immunoreactivity in both breast cancer cells and endothelial cells in and around the tumors (Fig. 1)Citation . Most of the immunopositive endothelial cells belonged to capillaries or other microvessels with no surrounding smooth muscle coat. Of the 118 specimens analyzed, 116 contained tumor tissue, and 104 also contained normal peritumoral tissue. ecNOS-positive microvascular counts were expressed as means of the six areas containing the highest ecNOS-positive microvascular densities in the tumoral (TEMVD; n = 116) and peritumoral tissue (PEMVD; n = 104). To test consensus, the same 41 blind-coded sections were counted by two independent observers, and a Wilcoxon signed rank test showed no significant difference between the two sets of results (P = 0.81, n = 41), whereas the Spearman rank correlation coefficient was 0.93 (P < 0.0001). This counting method was much quicker than the use of stereology for quantitating immunopositive endothelial cell densities. Moreover, stereology was very cumbersome to use for quantitating extratumoral endothelial densities because high magnifications were needed to ensure that completely tumor-free areas were being analyzed. Stereological analysis (point-counting with a grid) of tumoral ecNOS-positive endothelial cells correlated closely to TEMVD (Spearman rank correlation coefficient, 0.76; n = 116; P < 0.0001). We, therefore, conclude that these counts closely reflect immunopositive endothelial cell densities. TEMVD (median, 77.1 profiles per mm2; range, 0–472.3 profiles per mm2) correlated significantly to PEMVD (median, 50.9 profiles per mm2; range, 5.0–112.4 profiles per mm2; rank correlation, 0.48; n = 103; P < 0.0001) but not to age, ER status, PgR status, or tumor size. PEMVD correlated weakly (0.31) to PgR status (P = 0.04; n = 43) but not to age, ER status, or tumor size. Grouping TEMVD (n = 116) and PEMVD (n = 104) by quartiles and comparing to lymph node status produced {chi}2 values of 0.48 (P = 0.92) and 1.70 (P = 0.63), respectively, and comparing to grade of anaplasia produced {chi}2 values of 5.77 (P = 0.45) and 1.04 (P = 0.98), respectively.



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  		Fig. 1. Sections of human breast cancer specimens immunocytochemically stained for ecNOS and lightly counterstained with hematoxylin. a, strong ecNOS staining of scattered tumor cells. b, ecNOS staining of tumoral microvessels, no staining of tumor cells. c, ecNOS staining of microvessels in peritumoral tissue. x 150.

 
Patients <55 and >=55 years of age were analyzed separately because only the former were fully representative of the DBCG database. The was no difference in median between the two age groups with respect to either PEMVD (Wilcoxon rank sum, P = 0.56) or TEMVD (P = 0.12). In patients <55 years old, PEMVD used as a continuous variable or dichotomized by the median emerged as a significant prognostic factor that was independent of other parameters including lymph node status, tumor size, and grade of anaplasia (Tables 3Citation and 4Citation ). Only lymph node status and PEMVD provided independent prognostic information. The fact that lymph node status only reached borderline significance is most likely attributable to the small sample size. The estimated hazard ratios are, however, similar to those found in other DBCG studies (22) . In contrast, in patients >=55 years old, PEMVD did not emerge as a prognostic factor (Fig. 2)Citation . In these patients, only lymph node status emerged as a borderline prognostic factor for recurrence-free (P = 0.07) and overall (P = 0.05) survival. TEMVD and the percentage ecNOS-positive tumor cells did not offer prognostic information for patients either <55 or >=55 years old.


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  		Table 3 Analysis of recurrence-free survival in patients <55 years old (n = 54)a

 

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  		Table 4 Analysis of overall survival in patients <55 years old (n = 54)a

 


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  		Fig. 2. Kaplan-Meier plots of recurrence-free survival (a and b) and overall survival (c and d) in patients with low (LO) and high (HI) PEMVD stratified by age (a and c, <55 years old; b and d, >=55 years old) using single sections for counting. The number of events and the number of patients at risk (for a and b, times = 0, 24, 48, and 72 months; for c and d, times = 0, 48, 96, and 144 months) in each group are shown below the plots. The Ps are shown on each plot. The hazard ratios (with 95% confidence intervals) were as follows: recurrence-free survival <55 years, 0.31 (0.14–0.70); >=55 years, 0.88 (0.39–2.00); overall survival <55 years, 0.18 (0.07–0.48); >=55 years, 1.25 (0.61–2.58).

 
The influence of the heterogeneity of peritumoral tissue was assessed by analyzing a randomly selected smaller series of sections (n = 78) from the same patients for PEMVD. The rank correlation coefficient between the two sets was 0.35. In the new smaller series, PEMVD, dichotomized by the median, again emerged as an independent prognostic indicator for recurrence-free (P = 0.02) and overall (P = 0.05) survival, and the results also suggested an age dependency. The estimated hazard functions were very similar to the first series. Combining the results of both series led to a better discrimination for recurrence-free (P < 0.001) and overall (P < 0.0001) survival.


   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our results show that ecNOS is present both in breast cancer cells and in endothelial cells. The presence of ecNOS in the cancer cells themselves agrees with previous data (24 , 25) and with our own findings in cultured breast cancer cells.4 The production of ecNOS by mammary carcinoma cells has, thus, been established by immunocytochemistry and by RT-PCR followed by cloning and sequencing of the PCR product.4 No clear prognostic effect of ecNOS expression in breast cancer cells could be established. As previous studies have indicated that a high microvascular density in the tumor itself may be associated with a poor prognosis (20 , 21) we decided to count ecNOS immunoreactive profiles both inside and outside the tumor tissue per se. The results were highly reproducible and showed that the density of ecNOS-positive microvessels outside the tumor (PEMVD) was a significant and independent prognostic factor in patients <55 years old. If two different sections from each patient were used for counting, the predictive value of PEMVD was further increased. It was not possible to establish a clear prognostic effect of the tumoral ecNOS-positive microvascular density (TEMVD), possibly suggesting that overall tumor vascularity and ecNOS expression are oppositely acting variables. The patients <55 years of age were representative of patients registered in the DBCG database from the same period. In contrast, the patients above 55 years were not representative. We are, thus, hesitant to make conclusions from the latter group, but note that only lymph node status reached borderline significance here. The lack of prognostic value of PEMVD in those patients may, hence, either reflect the limitation of the material or a true biological difference.

Thus, our findings show that tumors surrounded by nonneoplastic tissue having a high density of ecNOS-positive microvessels are associated with a better recurrence-free and overall survival of patients <55 years old. This could reflect the fact that some patients express more ecNOS than others. Thus, it is known that many factors, including shear stress, transforming growth factor-ß, and estrogen, may stimulate ecNOS expression (16, 17, 18) . In addition, genetic factors may also control ecNOS expression (26) . Because ecNOS has been detected also in the endothelium of lymphatic vessels (27 , 28) , it is likely that the vessels quantitated in our study represent both blood and lymphatic microvessels. Importantly, many of the microvessels were devoid of media containing smooth muscle cells. Because these represent the target for the short-lived transmitter NO with respect to regulation of blood pressure, alternative roles for ecNOS in microvessels must be sought. Such roles may include regulation of endothelial permeability, angiogenesis, leukocyte and tumor cell adhesion, and active killing of tumor cells (3, 4, 5, 6, 7, 8) . Our present data are compatible with the view that certain patients, due to hormonal, genetic, or other factors, have a more efficient endothelial defense system against tumor invasion than others. Such NO-dependent defenses could include reduced tumor cell adhesion (3) and/or killing of adjacent tumor cells (5, 6, 7, 8) .


   ACKNOWLEDGMENTS
 
We thank Dr. K. West-Andersen of the DBCG Secretariat for assistance with the database and Drs. N. Brünner, K. Danø, S. Olesen Larsen, and J. Wohlfahrt for valuable discussions and comments and B. Scherfig and B. Traasdahl for expert technical assistance.


   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 study was supported by the Danish Medical Research Council and the Danish Cancer Society. Back

2 To whom requests for reprints should be addressed, at Institute of Anatomy and Physiology, The Royal Veterinary and Agricultural University Grønnegardsvej 7, DK-1870 Frederiksberg C, Denmark. Fax: 45 35 28 25 47; E-mail: Lail{at}kvl.dk Back

3 The abbreviations used are: NO, nitric oxide; NOS, NO synthase; ecNOS, endothelial cell NOS; DBCG, Danish Breast Cancer Cooperative Group; ER, estrogen receptor; PgR, progesterone receptor. Back

4 K. Mortensen, J. Skouv, D. M. Hougaard, and L-I. Larsson. Endogenous endothelial nitric oxide synthase modulates apoptosis in cultured breast cancer cells and is transcriptionally regulated by p53, submitted for publication. Back

Received 8/17/98; revised 12/17/98; accepted 1/29/99.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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