Cancer Research Meeting Calendar Protein Translation and Cancer
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yang, G.
Right arrow Articles by Thompson, T. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yang, G.
Right arrow Articles by Thompson, T. C.
[Cancer Research 64, 2076-2082, March 15, 2004]
© 2004 American Association for Cancer Research

Regular Articles

Reduced Infiltration of Class A Scavenger Receptor Positive Antigen-Presenting Cells Is Associated with Prostate Cancer Progression

Guang Yang1, Josephine Addai1, Wei-hua Tian1, Anna Frolov1, Thomas M. Wheeler2 and Timothy C. Thompson1,3,4

1 Scott Department of Urology, and 2 Departments of Pathology, 3 Molecular and Cellular Biology, and 4 Radiology, Baylor College of Medicine, Houston, Texas


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The class A macrophage scavenger receptor (SR-A) is expressed in antigen presenting cells and is involved in host immune responses. Germ-line mutation of this gene has been associated with increased risk of human prostate cancer. However, there is little known about its expression in normal or neoplastic human prostate tissues. Double immunofluorescent labeling with monoclonal antibodies to SR-A and specific macrophage and dendritic cell markers was used to identify cells expressing SR-A in human prostate tissues. SR-A immunohistochemical staining was performed on paraffin sections of normal prostate, prostatic intraepithelial neoplasia (PIN) lesions, and prostate cancers from radical prostatectomy specimens. SR-A was expressed in a subset of macrophages and dendritic cells that infiltrated prostatic tissues. The majority of SR-A-positive cells coexpressed CD68, and a relatively low percentage expressed S100 protein. The number of SR-A-positive cells was significantly increased in PIN as compared with normal prostatic tissue (P = 0.0176). In contrast, the number of SR-A-positive cells decreased with tumor progression. A lower SR-A-positive cell density was associated with higher clinical stage ({rho} = -0.26; P = 0.0234). Inverse associations were also found between SR-A density and positive lymph nodes ({rho} = -0.23; P = 0.0437), tumor size ({rho} = -0.31; P = 0.0100) and preoperative PSA levels ({rho} = -0.32; P = 0.0057). SR-A density is a significant predictor of disease-free survival after surgery univariately (P = 0.0003), as well as multivariately, adjusted for known clinical and pathological markers including preoperative prostate-specific antigen, clinical stage, Gleason score, surgical margin, extraprostatic extension, and seminal vesicle invasion, as well as lymph node metastasis (P = 0.0021). The preferential accumulation of SR-A-positive cells in PIN suggests a role for SR-A in the APC response to early malignancy. A reduction in the number of SR-A-positive cells demarcates tumor progression as indicated by clinical and pathological correlations. Our results additionally indicate that systematic measurement of SR-A density is a strong prognostic marker for clinical outcome after surgery.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Chronic or recurrent infection caused by bacteria or viruses has been suggested as an etiologic factor of human prostate cancer (1) . This notion has been supported by epidemiological findings indicating that patients with prostatitis or sexually transmitted disease are at higher risk for prostate cancer (2, 3, 4) and some pathological observations that indicate frequent coexistence of prostatic infection/inflammation with premalignant lesions and localized prostate cancers (5 , 6) . A causal relationship between inflammation/innate immunity and cancer has become more widely accepted, yet the molecular and cellular mechanisms that underpin this relationship remain largely unresolved (7) . The possible link between inflammatory changes and prostate cancer risk received some support from recent genetic studies, which identified germ-line mutations of the class A macrophage scavenger receptor (SR-A) gene that is involved in host defense immunity as associated with increased risk of prostate cancer (8 , 9) . It was postulated that defective expression of SR-A, which is associated with macrophage function, could lead to uncontrolled inflammatory damages resulting in malignancy.

The SR-A gene (also known as macrophage scavenger receptor I, MSR1) is located on short arm of chromosome 8p22, a site linked to some hereditary prostate cancers (10) . It encodes multiple SR-A isoforms generated by alternative splicing (11) . The type 1 and 2 SR-A isoforms are multidomain, trimeric cell membrane glycoproteins that can recognize multiple ligands including modified lipoproteins, polyguanylic acid, polyinosinic acid, polysaccharide, and other polyanionic molecules (12 , 13) . Because of the broad spectrum of ligands, SR-A is multifunctional (13) . SR-A is able to mediate the uptake of modified low-density lipoproteins involved in lipid metabolism and arteriosclerosis (14 , 15) . As one of the pattern recognition molecules on the surface of macrophages, SR-A is capable of recognizing bacteria and, thus, is involved in host innate immunity (16 , 17) . SR-A has also been shown to function in uptake and clearance of various cellular components and apoptotic cells, suggesting a role in tissue homeostasis (18) . Although SR-A is predominantly localized to macrophages, its expression in vascular endothelial cells, smooth muscle cells, fibroblasts, and cultured dendritic cells has been reported (19, 20, 21) . However, little is known about SR-A expression or its localization pattern in normal human prostatic tissues. Furthermore, to our knowledge, there has been no study directly addressing its functional role in prostate cancer.

In this study we document SR-A protein expression in both normal and neoplastic human prostates using immunohistochemical techniques. We show that SR-A expression is associated with antigen-presenting cells including both macrophages and dendritic cells. We also demonstrate that SR-A-positive cells infiltrate prostatic intraepithelial neoplasia (PIN) lesions at significantly higher densities compared with normal tissues. Importantly, significant inverse associations between the SR-A-positive cells and the clinical/pathological features of prostate cancer and patient clinical outcome are also demonstrated.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients and Tissue Processing.
Paraffin sections from 5 normal prostates obtained from organ donors, 9 prostates obtained at cystoprostatectomy in which there were PIN lesions but no detectable local cancers, and 90 prostate cancer specimens obtained at radical prostatectomy were used in this study. The specimens were obtained from the Specialized Program of Research Excellence Tissue Bank, The Methodist Hospital, Baylor College of Medicine. Patients who had undergone radical prostatectomy were age 45–77 years (mean, 63). No patient received any treatment for cancer before surgery that was done by a single surgeon between 1983 and 1996. The Institutional Review Board-approved consent forms were used to obtain assent from the patients. Preoperatively, the patients had a cancer staged according to the Unio Internationale Contra Cancrum clinical staging system (1992) as T1a-c (n = 21), T2a-c (n = 44), and T3a (n = 13). After the surgery, the prostate specimens were sliced into 5-mm-thick tissue blocks as described previously (22) . The tissue blocks were then fixed in 10% formalin and embedded in paraffin. H&E-stained sections from each tissue block were evaluated by a single pathologist (T. M. W.) for tumor histological differential status as demonstrated by Gleason score and pathological stage (Tumor-Node-Metastasis system). The index cancers were identified and used for immunohistochemistry. Recurrence was defined as a postoperative prostate-specific antigen (PSA) level >0.4 ng/ml (Hybritech, Inc., San Diego, CA) on two successive measurements.

Immunohistochemistry.
The prostate sections were deparaffined and rehydrated. They were then heated in citrate buffer (0.01 M; pH 2.0) within an 800 W microwave oven for 12 min for antigen retrieval. Endogenous peroxidase in sections was inactivated in 2% H2O2 for 10 min. The sections were then blocked in 3% normal horse serum in 0.2 M PBS (pH 7.4) and followed by incubation in monoclonal antibody to human SR-A (TransGenic, Inc., Kumamoto, Japan). This antibody recognizes the recombinant human SR-A corresponding to amino acid residues 131–451 of SR-A and was able to react with both the type 1 and type 2 isoforms (23) . This antibody was diluted 1:25 in PBS with 0.5% normal horse serum. The sections were incubated in the primary antibody for 2 h at room temperature. They were then processed after standard avidin-biotin complex immunostaining procedures with an ABC kit (Vector Laboratories, Burlingame, CA). Immunoreaction products were visualized in a 3,3'-diaminobenzidine/H2O2 solution. The specificity of the immunoreactions was confirmed by the negative results from adjacent sections that were incubated either in PBS or in normal mouse serum replacing the specific antibodies. Immunofluorescent double labeling was performed as for single staining for SR-A up to the first primary antibody incubation. Sections were then incubated with biotinylated goat antimouse IgG (1:100) for 40 min, followed by incubation in FITC-conjugated streptavidin (Zymed) for 30 min. After washing twice in PBS the sections were reblocked in 1.5% horse serum for 20 min and incubated with the monoclonal antibody either to S100 or to CD68 (Dako, Glostrup, Denmark) for 60 min. The S100 and CD68 antibodies were detected with Cy-3 conjugated donkey antimouse IgG (Jackson ImmunoResearch Lab.). Sections were visualized using a fluorescence microscope. Specificity of double labeling was verified by replacing S100 or CD68 antibody with normal mouse serum.

Histological Analysis.
SR-A-positive cells were quantified by systematically screening the entire cancer. All of the counting was done without knowledge of the clinical information. For each specimen 15–30 ocular measuring fields, each composed of 100 grids and having a real area of 0.0625 mm2 were randomly chosen under a microscope at a power of x400 within a cancer. Sections were positioned such that each measuring field was completely occupied by only cancer tissue. All of the SR-A-positive cells in each measuring field were counted and stratified as those localized to cancer stroma versus those in contact with cancer cells or penetrating into a cancer lumen. The number of SR-A-positive cells per mm2 of total cancer tissue area was defined as SR-Atotal. The number of stromal SR-A-positive cells per mm2 of cancer stroma area was recorded as SR-Astroma. Similarly, SR-Acancer was determined from the number of SR-A-positive cells per mm2 in the cancer cell compartment. From each of the normal and PIN specimens, 5–20 measuring fields over glandular epithelia and their surrounding stroma were evaluated, and SR-A-positive cells were counted and expressed as SR-Atotal.

Statistical Analysis.
The correlation of SR-A-positive cells with pathological and clinical variables was evaluated using the Spearman’s correlation coefficient testing. One-way ANOVA was used to compare means of CD68 and S100 percentages between three types of tissue. Comparisons in SR-Atotal among normal, PIN, and prostate cancer specimens were made using Mann-Whitney test. Univariate analysis of SR-A levels as continuous markers and multivariate analyses were performed using the Cox proportional hazard regression model. The hazard ratio and its 95% confidence interval were recorded for each marker. Survival curves of relapse-free survival were obtained using a Kaplan-Meier analysis and tested by log-rank test. Ps < 0.05 were considered statistically significant in all of the analyses. All of the analyses were performed with statistical software SPSS 11.0 (SPSS Inc., Chicago, IL).


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
SR-A Is Localized to a Subset of Macrophages and Dendritic Cells in Normal Prostatic Tissues and in Prostate Cancer.
SR-A expression was detected in all of the prostate samples analyzed including normal prostate, PIN, and prostate cancer specimens. SR-A was localized to the cell membrane and cytoplasm of mononuclear cells in all of the specimens (Fig. 1)Citation . In normal and neoplastic prostate tissues, SR-A-positive cells mainly infiltrated prostatic stroma, and to a lesser extent, the epithelia. SR-A-positive cells exhibited morphological features similar to those of macrophages, although they appeared to have a smaller average size than macrophages. Infrequently, some SR-A-positive cells with vascular endothelial cell features were also observed. To determine the fraction of SR-A-positive macrophages we used antibodies specifically for SR-A and for CD68, a glycoprotein primarily expressed in macrophages (24) in double-labeling analysis of 5 normal, 6 PIN, and 12 cancer specimens (Fig. 2)Citation . Although highly variable, the SR-A-positive/CD68-positive cell fraction was 30.3, 28.3, and 36.3 median percent in normal, PIN, and tumor tissues, respectively. These differences were not statistically significant. Within the SR-A-positive cell group, the majority of cells were immunoreactive for antibody to CD68 (Table 1)Citation . The mean values of the CD68-positive/SR-A-positive cell fraction were 93, 90.5, and 93.3% in normal, PIN, and tumor specimens, respectively. The differences between tissue groups were not statistically significant (P = 0.2430). To determine whether the CD 68-negative/SR-A-positive cells contained a dendritic cell subpopulation, some sections were double-labeled with SR-A antibody and S100 antibody (Fig. 3)Citation , which recognizes Langerhans cells, a subset of dendritic cells present in multiple organs including human prostate (25) . The results indicated that the mean fraction of S100-positive/SR-A-positive cells was 14.6, 16.4, and 14.2% in normal, PIN, and prostate cancer specimens, respectively. These differences were not statistically significant (P = 0.8401). Overall, these results suggest that in benign and neoplastic human prostate tissues SR-A-positive cells predominantly represent macrophages together with a small subset of specialized dendritic cells.



View larger version (149K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 1. Avidin-biotin complex immunostaining demonstrating scavenger receptor class A expression in human prostate using a monoclonal antibody. Positively labeled cells are shown in normal prostate (A); a prostatic intraepithelial neoplasia lesion (B); prostate cancer (C); and areas of inflammation within a benign prostate (D and E). Original magnification, A–D: x200; E: x400.

 


View larger version (106K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 2. Double immunofluorescent labeling (C and F, superimposed image) demonstrating scavenger receptor class A (SR-A; A and D) and CD68 (B and E) expression in the same section of two independent prostate cancer specimens. There was a significantly higher percentage of CD68-positive cells that were SR-A positive in some cancers (example shown in A–C) compared with others in which only a small percentage of the CD68-positive cells expressed SR-A (example shown in D–F). Original magnification: x200.

 

View this table:
[in this window]
[in a new window]

  		Table 1 CD68 and S100 protein expression in SR-Aa-positive cells

Immunofluorecence double labeling using SR-A and CD68 or SR-A and S100 antibodies was performed on the same sections from normal, PIN or prostate cancers. SR-A positive cells were screened in each specimen for CD68 and S100 expression.

 


View larger version (71K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 3. Double immunofluorescent labeling (C, superimposed image) demonstrating colocalization of scavenger receptor class A (A) and S100 (B) expression in some tumor infiltrating mononuclear cells. Original magnification: x400.

 
In Benign Prostatic Tissues SR-A Positive Cells Accumulate in Areas of Inflammation and in PIN Lesions.
In normal prostatic tissues from organ donor specimens the number of SR-A-positive cells was low, with the majority of cells present in the stroma, and a relatively small fraction present in the glandular epithelium and lumens (Fig. 1A)Citation . However, in the benign prostatic tissues from cystoprostatectomy specimens significantly higher numbers of SR-A-positive cells accumulated in the areas undergoing inflammatory changes (Fig. 1D)Citation Some of the SR-A-positive cells penetrated into the lumens and displayed features of foamy cells (Fig. 1E)Citation . SR-A-positive cells infiltrated PIN lesions at significantly higher densities compared with normal prostatic tissues from organ donors (P = 0.0167) or prostate cancers (P = 0.0012; Fig. 4Citation ). In prostate cancer specimens, tumor-associated SR-A-positive cells were distributed in distinguishable compartments i.e., the tumor-associated stroma or cancer cell region in which they are in direct contact with cancer cells or were penetrating into cancer cell lumens. In malignant tissues the majority of SR-A-positive cells were distributed within the tumor-associated stroma.



View larger version (16K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 4. Box plot representation of densities of the scavenger receptor class A (SR-A)-positive cells (SR-Atotal) in normal prostate (Normal), prostatic intraepithelial neoplasia (PIN), and prostate cancer (Cancer) specimens. *, P = 0.0176 as compared with normal prostate specimens.

 
Correlation of SR-A-Positive Cells with Clinical Parameters and Tumor Pathology.
Among the 90 cancer specimens examined, 78 had complete pathological and clinical follow-up information and, therefore, were used for correlation analyses. This cohort consisted of patients with 52 (67%) having positive extracapsular extension, 22 (28%) having positive seminal vesicle invasion, 15 (19%) having positive lymph nodes, and 18 (23%) having positive margins. Clinical stages were distributed as 21 (27%) T1, 44 (56%) T2, and 13 (17%) T3a. Seven patients (9%) had Gleason score <6, 19 patients (24%) had Gleason score 6, 36 patients (46%) had Gleason score 7, and 16 patients (20.5%) had >7. Preoperative PSA levels (ng/ml) ranged from 0.7 to 100 with a mean level of 15.0 and median of 10.5. Tumor volumes (ml) ranged from 0.9 to 20.18 with mean volume of 4.3 and median of 2.8. The numerical densities of SR-A-positive cells in stromal or cancer cell compartments, as well as in total tumor area were recorded as SR-Astroma, SR-Acancer, or SR-Atotal, respectively. In general, patients with cancers of relatively high clinical stage, a higher Gleason score, seminal vesicle invasion, or lymph node involvement tended to have relatively lower SR-Atotal and/or SR-Astroma, and some of these associations were found to be statistically significant (Table 2)Citation . The Spearman correlation analyses showed that both SR-Atotal and SR-Astroma were inversely correlated with clinical stage ({rho} = -0.26; P = 0.0234 and {rho} = -0.24; P = 0.0344, respectively). An inverse relationship was also found between SR-Atotal and tumor volume ({rho} = -0.31; P = 0.0100), lymph node involvement ({rho} = -0.23; P = 0.0445), and preoperative PSA levels ({rho} = -0.32; P = 0.0057). However, correlations between Gleason score and SR-Atotal , SR-Astroma, or SR-Acancer were not statistically significant (all Ps > 0.05).


View this table:
[in this window]
[in a new window]

  		Table 2 Correlation of SR-Aa-expressing cells with clinical and pathological parameters of prostate cancer

 
SR-Atotal Is a Predictor of Disease-Free Survival.
The recurrence-free follow-up time for the 78 cases ranged 0.8–131.7 months and averaged 47.75 months. Forty of the 78 patients (51%) had biological recurrences (PSA >=0.4 ng/ml, on two successive measurements) during follow up. The value of SR-Atotal, SR-Astroma, or SR-Acancer as a continuous predictive marker for recurrence was analyzed separately in this set of patients using the Cox proportional hazard regression model. Univariately, only the SR-Atotal but not SR-Acancer or SR-Astroma was significantly inversely associated with disease-free survival [hazard ratio (HR) = 0.983; HR-1 = 1.017; P = 0.0003; Table 3Citation ). The inversed hazard ratio of 1.017 means that for every 10 units reduction in SR-Atotal risk of experiencing a recurrence (estimated by HR) during the follow-up time increases by 17%. The SR-Atotal data of this cohort were additionally stratified with the median value of 72.8/mm2 as a cutoff point, with 39 cases (50%) falling into the low category (SR-Atotal <= 72.8), and 39 cases (50%) falling into the high (SR-Atotal >72.8) category. A highly significant association of the low SR-Atotal category with poor disease-free survival was established by the univariate analysis [HR = 0.238; HR-1 = 3.58; P = 0.0002; Table 3Citation ). Thus, a patient with a SR-Atotal level <=72.8/mm2 had 3.6 times more chances of experiencing a recurrence during the follow-up time than a patient with a high SR-Atotal level. This difference in risk can be also observed on the Kaplan-Meier plot (Fig. 5)Citation . When SR-Astroma was stratified using the median (<=154.92 or >154.92/mm2) as cutoff, similar results were observed: patients with low expression had 2.8 times more chances of experiencing a recurrence during the follow-up time (P = 0.0021). These results strongly support the hypothesis that high densities of SR-A-positive cells within the total cancer area and cancer stroma were associated with a lower rate of recurrence after surgery. In this series of patients, other known predictors of recurrence-free survival including extracapsular extension, seminal vesicle invasion, lymph node metastasis, surgical margin status, preoperative PSA level, tumor volume, and Gleason score were all significant predictors in univariate analyses, as expected. Multivariate analysis that included SR-Atotal and all of the above parameters showed that SR-Atotal is a very strong independent predictor of disease progression when used either as a continuous or a grouped variable. For any two patients with identical clinical/pathological characteristics, a patient with low levels (72.8/mm2) of SR-Atotal had a 4.9 times greater chance of experiencing a recurrence during the follow-up time than a patient with high levels (P = 0.0007), whereas for every 10-unit decrease in SR-Atotal this risk increased by 23% (P = 0.0029). A similar conclusion could be drawn from multivariate analysis of SR-Astroma, showing a 2.3 times higher risk of recurrence for patients with low SR-Astroma (<=154.92 mm2; P = 0.049; Table 3Citation ). These results indicate that high densities of SR-A-positive cells within the total cancer area and stroma as indicated by SR-Atotal and SR-Astroma are independent predictors of a lower recurrence rate after surgery.


View this table:
[in this window]
[in a new window]

  		Table 3 Univariate and multivariate Cox Proportional hazards model for time to recurrence

 


View larger version (16K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 5. A, recurrence-free survival probability after radical prostatectomy for patients with high or low expression levels of scavenger receptor class A (SR-A) in total cancer area (SR-Atotal) stratified according to the median value of SR-Atotal (<=72.8 or >72.8). B, recurrence-free survival probability after radical prostatectomy for patients with high or low expression levels of SR-A in cancer-associated stroma (SR-Astroma) stratified according to the median value of SR-Astroma (<=154.92 or >154.92).

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study we showed that SR-A is expressed in a subset of macrophages and dendritic cells in human prostate tissues. Both cell types can be categorized as APCs, share the same origin from myeloid cells in bone marrow, and have overlapping antigen-processing functions (26) . This expression pattern suggests a close association between the function of SR-A and activities of APCs. In benign prostatic tissues, SR-A-positive cell infiltrates were minimal and present in active inflammatory lesions, supporting the well-documented role of SR-A in immune cell-mediated host defense. SR-A-positive cells infiltrated PIN lesions at significantly higher densities compared with normal or malignant prostatic tissues. This result is intriguing, yet its biological significance is not immediately apparent. Although there is a report that proposed a link between the chronic inflammation-associated, proliferative atrophy in human prostate with PIN lesions (6) , to our knowledge inflammatory activities have not been specifically correlated with PIN lesions. Interestingly, relatively high levels of apoptosis occur in PIN as well as in prostate cancer (27) . Yet increased apoptosis is accompanied by increased mitosis such that a net gain in cell number is achieved in both neoplastic lesions (28) . APCs including both macrophages and dendritic cells are capable of uptake of apoptotic cells (29 , 30) , and a role for several members of the scavenger receptor family in this process has been identified (18 , 31 , 32) . In addition to capturing tumor-associated antigens by phagocytosis, dendritic cells also capture antigens from live cells through a process referred to as "nibbling" (33) . Dendritic cells are able to "nibble" and internalize gp100 tumor antigen expressed at the surface of viable adenocarcinoma cells via a SR-A-mediated mechanism (21) . Thus, the present study demonstrating increased numbers of SR-A-positive cells infiltrating PIN lesions compared with normal prostatic tissues may reflect increased APC activities during the transition to malignancy.

Another important result of this study is the demonstration of down-regulation of SR-A expression during cancer progression. Reduced numbers of SR-A-positive APCs are associated with higher clinical stage, larger tumor size, and elevated PSA levels in prostate cancer patients. The patients with relatively low levels of SR-A-positive APCs tended to develop lymph node metastasis and have a reduced probability of recurrence-free survival after surgery. The reduction of SR-A-positive APCs during progression might be a result of a generalized reduction in macrophage and/or dendritic cell infiltration (34) . In malignancies from a variety of organs including gastric, lung, and endometrial carcinoma, as well as squamous cell carcinoma of the oral cavity, APC populations identified by S100 antibody are also found to be relatively diminished (35, 36, 37, 38) . However, a comparison of the number of SR-A-positive cells with the number of CD68-positive macrophages generated from the same set of specimens (34) revealed some unique correlates of SR-A-positive cells. Although the density of CD68-positive macrophages within total cancer area (M{phi}total) correlates positively with SR-A-positive APCs (SR-Atotal; {rho} = 0.81; P < 0.001), these two cell populations do not always correlate with each other when segregated according to cancer compartments, i.e., cancer stroma or cancer cell-specific (see "Materials and Methods") and cancer Gleason score. The density of CD68-positive macrophages in close contact with cancer cells, i.e., M{phi}cancer, was correlated positively with Gleason score (34) , yet this relationship was not seen with SR-Acancer. As a result, the ratio of the two measurements (SR-Acancer/M{phi}cancer) in poorly differentiated cancer (Gleason score > 7) was 0.27, which was significantly lower than that of less aggressive cancer (Gleason score < 7; 0.47; P < 0.05). This suggests that the down-regulation in SR-A expression during progression is specifically related to cancer virulence and does not merely reflect reduced overall macrophage/dendritic cell infiltration.

It is possible to propose candidates for the factors that lead the progression-associated down-regulation of SR-A expression. It has been reported recently that expression of some scavenger receptors may be regulated by specific cytokines. Transforming growth factor ß1, a well-known immune suppressor, has been found able to specifically inhibit SR-A but not SR-B expression in a human monocytes/macrophage cell line, THP-1 (39 , 40) . Our previous study and other reports have demonstrated that a significantly elevated transforming growth factor ß1 level in prostate cancer cells is associated with tumor progression and metastasis (41, 42, 43) . Interleukin 6 has also been reported recently to be capable of inhibiting SR-A expression in THP-1 cells at both mRNA and protein levels (44) . Interestingly, there is accumulating evidence that interleukin 6 expression in cancer cells is progressively increased with increasing malignant potential and positively associated with metastasis (45 , 46) . Thus, it seems reasonable to assume that transforming growth factor ß1 and/or interleukin 6 may suppress SR-A expression in the antigen-presenting cells in human prostate cancer.

The finding that there is a down-regulation of SR-A expressing during cancer progression has important implications in developing cancer immunotherapeutics. Because SR-A may be involved in tumor antigen processing (21) , an impaired or insufficient SR-A expression in APCs could directly jeopardize the processing of tumor antigen and thereby compromise host immune surveillance of malignant cells, and ultimately, lead to an attenuated host antitumor immune response. It is conceivable that normal SR-A expression and function in APCs is necessary to achieve optimal responses in specific immunotherapy protocols for prostate cancer. The finding showing the progression-associated SR-A down-regulation also has clinical relevance, because the measurement of the SR-Atotal was found to be independently predictive for recurrence-free survival in the patients after surgery. These results warrant additional studies on a larger, randomly selected population in both retrospective and prospective studies to establish its value as a clinical biomarker for prognosis of human prostate cancer.


   ACKNOWLEDGMENTS
 
We thank Terry L. Timme for critically reading the manuscript.


   FOOTNOTES
 
Grant support: Department of Defense (DAMD17–02-1–0011) and a Specialized Program of Research Excellence (SPORE) Grant from the National Cancer Institute (P50–58204).

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.

Requests for reprints: Timothy C. Thompson, Scott Department of Urology, Baylor College of Medicine, 6560 Fannin, Suite 2100, Houston, TX 77030. Phone: (713) 799-8718; Fax: (713) 794-7983; E-mail: timothyt{at}www.urol.bcm.tmc.edu

Received 12/30/03. Accepted 1/ 9/04.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Roseman DS, Ansell JS, Chapman WH. Sexually transmitted diseases and carcinogenesis. Urol Clin North Am, 11: 27-43, 1984.[Medline]
  2. Dennis LK, Lynch CF, Torner JC. Epidemiologic association between prostatitis and prostate cancer. Urology, 60: 78 2002.
  3. Hayes RB, Pottern LM, Strickler H, et al Sexual behaviour, STDs and risks for prostate cancer. Br J Cancer, 82: 718 2000.[CrossRef][Medline]
  4. Dennis LK, Dawson DV. Meta-analysis of measures of sexual activity and prostate cancer. Epidemiology, 13: 72 2002.[CrossRef][Medline]
  5. Putzi MJ, De Marzo AM. Morphologic transitions between proliferative inflammatory atrophy and high-gride prostatic intraepithelial neoplasia. Urology, 56: 828-32, 2000.[CrossRef][Medline]
  6. De Marzo AM, Marchi VL, Epstein JI, Nelson WG. Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis. Am J Pathol, 155: 1985 1999.[Abstract/Free Full Text]
  7. Coussens LM, Werb Z. Inflammation and cancer. Nature (Lond), 420: 860-7, 2002.[CrossRef][Medline]
  8. Xu J, Zheng SL, Komiya A, et al Common sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk. Am J Hum Genet, 72: 208-12, 2003.[CrossRef][Medline]
  9. Xu J, Zheng SL, Komiya A, et al Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk. Nat Genet, 32: 321-5, 2002.[CrossRef][Medline]
  10. Bova GS, MacGrogan D, Levy A, Pin SS, Bookstein R, Isaacs WB. Physical mapping of chromosome 8p22 markers and their homozygous deletion in a metastatic prostate cancer. Genomics, 35: 46-54, 1996.[CrossRef][Medline]
  11. Platt N, Haworth R, Darley L, Gordon S. The many roles of the class A macrophage scavenger receptor. Int Rev Cytol, 212: 1-40, 2002.[Medline]
  12. Podrez EA, Hoppe G, O’Neil J, Sayre LM, Sheibani N, Hoff HF. Macrophage receptors responsible for distinct recognition of low density lipoprotein containing pyrrole or pyridinium adducts: models of oxidized low density lipoprotein. J Lipid Res, 41: 1455-63, 2000.[Abstract/Free Full Text]
  13. Platt N, Gordon S. Is the class A macrophage scavenger receptor (SR-A) multifunctional? - The mouse’s tale. J Clin Invest, 108: 649-54, 2001.[CrossRef][Medline]
  14. Babaev VR, Gleaves LA, Carter KJ, et al Reduced atherosclerotic lesions in mice deficient for total or macrophage-specific expression of scavenger receptor-A. Arterioscler Thromb Vasc Biol, 20: 2506-8, 2000.[Free Full Text]
  15. Kunjathoor VV, Febbraio M, Podrez EA, et al Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages. J Biol Chem, 277: 49982-8, 2002.[Abstract/Free Full Text]
  16. Peiser L, De Winther MP, Makepeace K, et al The class A macrophage scavenger receptor is a major pattern recognition receptor for Neisseria meningitidis which is independent of lipopolysaccharide and not required for secretory responses. Infect Immun, 70: 5346-54, 2002.[Abstract/Free Full Text]
  17. Haworth R, Platt N, Keshav S, et al The macrophage scavenger receptor type A is expressed by activated macrophages and protects the host against lethal endotoxic shock. J Exp Med, 186: 1431-9, 1997.[Abstract/Free Full Text]
  18. Platt N, Suzuki H, Kurihara Y, Kodama T, Gordon S. Role for the class A macrophage scavenger receptor in the phagocytosis of apoptotic thymocytes in vitro. Proc Natl Acad Sci USA, 93: 12456-60, 1996.[Abstract/Free Full Text]
  19. Baker DP, Vanlenten BJ, Fogelman AM, Edwards PA, Kean C, Berliner JA. LDL, scavenger and b-VLDL receptors on aortic endothelia cells. Arteriosclerosis, 4: 248-55, 1984.[Abstract/Free Full Text]
  20. Pitas RE. Expression of the acetyl low-denisty –lipoprotein receptor by rabbit fibroblasts and smooth muscle cells: up-regulation by phorbol esters. J Biol Chem, 265: 12722-7, 1990.[Abstract/Free Full Text]
  21. Harshyne LA, Zimmer MI, Watkins SC, Barratt-Boyes SM. A role for class a scavenger receptor in dendritic cell nibbling from live cells. J Immunol, 170: 2302-9, 2003.[Abstract/Free Full Text]
  22. Wheeler TM, Lebovitz RM. Fresh tissue harvest for research from prostatectomy specimens. Prostate, 25: 274-9, 1994.[Medline]
  23. Tomokiyo R, Jinnouchi K, Honda M, et al Production, characterization, and interspecies reactivities of monoclonal antibodies against human class A macrophage scavenger receptors. Atherosclerosis, 161: 123-32, 2002.[CrossRef][Medline]
  24. Pulford KA, Sipos A, Cordell JL, Stross WP, Mason DY. Distribution of the CD68 macrophage/myeloid associated antigen. Int Immunol, 2: 973-80, 1990.[Abstract/Free Full Text]
  25. Bigotti G, Coli A, Castagnola D. Distribution of Langerhans cells and HLA class II molecules in prostatic carcinomas of different histopathological grade. Prostate, 19: 73-87, 1991.[Medline]
  26. Mantovani A, Bottazzi B, Colotta F, Sozzani S, Ruco L. The origin and function of tumor-associated macrophages. Immunology Today, 13: 265-70, 1992.[CrossRef][Medline]
  27. Wheeler TM, Rogers E, Aihara M, Scardino PT, Thompson TC. Apoptotic index as a biomarker in prostatic intraepithelial neoplasia (PIN) and prostate cancer. J Cell Biochem Suppl, 19: 202-7, 1994.[Medline]
  28. Aihara M, Truong LD, Dunn JK, Wheeler TM, Scardino PT, Thompson TC. Frequency of apoptotic bodies positively correlates with Gleason grade in prostate cancer. Hum Pathol, 25: 797-801, 1994.[CrossRef][Medline]
  29. Platt N, da Silva RP, Gordon S. Recognizing death: the phagocytosis of apoptotic cells. Trends Cell Biol, 8: 365-72, 1998.[CrossRef][Medline]
  30. Nouri-Shirazi M, Banchereau J, Bell D, et al Dendritic cells capture killed tumor cells and present their antigens to elicit tumor-specific immune responses. J Immunol, 165: 3797-803, 2000.[Abstract/Free Full Text]
  31. Platt N, da Silva RP, Gordon S. Class A scavenger receptors and the phagocytosis of apoptotic cells. Immunol Lett, 65: 15-9, 1999.[CrossRef][Medline]
  32. Brown SB, Clarke MC, Magowan L, Sanderson H, Savill JI. Constitutive death of platelets leading to scavenger receptor-mediated phagocytosis. A caspase-independent cell clearance program. J Biol Chem., 275: 5987-96, 2000.[Abstract/Free Full Text]
  33. Harshyne LA, Watkins SC, Gambotto AS, Barratt-Boyes M. Dendritic cells acquire antigens from live cells for cross-presentation to CTL. J Immunol, 166: 3717-23, 2001.[Abstract/Free Full Text]
  34. Shimura S, Yang G, Ebara S, Wheeler TM, Frolov A, Thompson TC. Reduced infiltration of tumor-associated macrophages in human prostate cancer: association with cancer progression. Cancer Res, 60: 5857-61, 2000.[Abstract/Free Full Text]
  35. Tsujitani S, Kakeji Y, Watanabe A, Kohnoe S, Maehara Y, Sugimaghi K. Infiltration of S-100 protein positive dendritic cells and peritoneal recurrence in advanced gastric cancer. Int Surg, 77: 238-41, 1992.[Medline]
  36. Zeid NA, Muller HK. S100 positive dendritic cells in human lung tumors associated with cell differentiation and enhanced survival. Pathology, 25: 338-43, 1993.[Medline]
  37. Coppola D, Fu L, Nicosia SV, Kounelis S, Jones M. Prognostic significance of p53, bcl-2, vimentin and S100-protein-positive Langerhans cells in endometrial carcinoma. Hum Pathol, 29: 455-62, 1998.[CrossRef][Medline]
  38. Kikuchi K, Kusama K, Taguchi K, et al Dendritic cells in human squamous cell carcinoma of the oral cavity. Anticancer Res, 22: 545-57, 2002.[Medline]
  39. Nishimura N, Harada-Shiba M, Tajima S, et al Acquisition of secretion of transforming growth factor-ß 1 leads to autonomous suppression of scavenger receptor activity in a monocyte-macrophage cell line, THP-1. J Biol Chem, 273: 1562-7, 1998.[Abstract/Free Full Text]
  40. Draude G, Lorenz RL. TGF-ß1 downregulates CD36 and scavenger receptor A but upregulates LOX-1 in human macrophages. Am J Physiol Heart Circ Physiol, 278: H1042-8, 2000.[Abstract/Free Full Text]
  41. Truong LD, Kadmon D, McCune BK, Flanders KC, Scardino PT, Thompson TC. Association of transforming growth factor-ß 1 with prostate cancer: an immunohistochemical study. Hum Pathol, 24: 4-9, 1993.[CrossRef][Medline]
  42. Eastham JA, Truong LD, Rogers E, Kattan M, Flanders KC, Scardino PT, Thompson TC. Transforming growth factor-ß 1: comparative immunohistochemical localization in human primary and metastatic prostate cancer. Lab Invest, 3: 628-35, 1995.
  43. Wikstrom P, Stattin P, Franck-Lissbrant I, Damber JE, Bergh A. Transforming growth factor ß1 is associated with angiogenesis, metastasis, and poor clinical outcome in prostate cancer. Prostate, 37: 19-29, 1998.[CrossRef][Medline]
  44. Liao HS, Matsumoto A, Itakura H, et al Transcriptional inhibition by interleukin-6 of the class A macrophage scavenger receptor in macrophages derived from human peripheral monocytes and the THP-1 monocytic cell line. Arterioscler Thromb Vasc Biol, 19: 1872-80, 1999.[Abstract/Free Full Text]
  45. Adler HL, McCurdy MA, Kattan MW, Timme TL, Scardino PT, Thompson TC. Elevated levels of circulating interleukin-6 and transforming growth factor-ß1 in patients with metastatic prostatic carcinoma. J Urol, 161: 182-7, 1999.[CrossRef][Medline]
  46. Nakashima J, Tachibana M, Horiguchi Y, et al Serum interleukin 6 as a prognostic factor in patients with prostate cancer. Clin Cancer Res, 6: 2702-6, 2000.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 FASEB J.Home page
E. Herczenik and M. F. B. G. Gebbink
Molecular and cellular aspects of protein misfolding and disease
FASEB J, July 1, 2008; 22(7): 2115 - 2133.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
M. de la Luz Garcia-Hernandez, A. Gray, B. Hubby, O. J. Klinger, and W. M. Kast
Prostate Stem Cell Antigen Vaccination Induces a Long-term Protective Immune Response against Prostate Cancer in the Absence of Autoimmunity
Cancer Res., February 1, 2008; 68(3): 861 - 869.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M. S. Arredouani, F. Franco, A. Imrich, A. Fedulov, X. Lu, D. Perkins, R. Soininen, K. Tryggvason, S. D. Shapiro, and L. Kobzik
Scavenger Receptors SR-AI/II and MARCO Limit Pulmonary Dendritic Cell Migration and Allergic Airway Inflammation
J. Immunol., May 1, 2007; 178(9): 5912 - 5920.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Y.-L. Lin, W. J. S. de Villiers, B. Garvy, S. R. Post, T. R. Nagy, F. F. Safadi, M. C. Faugere, G. Wang, H. H. Malluche, and J. P. Williams
The Effect of Class A Scavenger Receptor Deficiency in Bone
J. Biol. Chem., February 16, 2007; 282(7): 4653 - 4660.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Yang, G.
Right arrow Articles by Thompson, T. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yang, G.
Right arrow Articles by Thompson, T. C.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online