SEARCH

SEARCH BY CITATION

Keywords:

  • KAI1/CD82;
  • nonsmall cell lung carcinoma;
  • prognosis;
  • immunohistochemistry;
  • metastasis suppressor gene

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

BACKGROUND

The KAI1/CD82 gene, the product of which is a member of the transmembrane-4 superfamily, is a suppressor of metastasis; as a result, it is inversely associated with tumor progression and is a favorable prognostic factor in some tumors. This study was performed to determine the prognostic value of KAI1/CD82 protein levels in nonsmall cell lung carcinoma (NSCLC). In addition, levels of KAI1/CD82 expression in metastatic lesions were determined and compared with those in primary NSCLC lesions.

METHODS

KAI1/CD82 expression in 200 NSCLC patients who underwent potentially curative surgery was immunohistochemically detected with C33, an anti-KAI1/CD82 monoclonal antibody. According to the degree of KAI1/CD82 positive cancer cells within the tumor tissue, each sample was classified as KAI1/CD82 positive, KAI1/CD82 reduced, or KAI1/CD82 negative.

RESULTS

Sixty-five samples (32.5%) were KAI1/CD82 positive, 31 (15.5%) were reduced, and 104 (52%) were negative. There was no significant association between KAI1/CD82 expression and clinicopathologic factors, but patients who were positive for KAI1/CD82 expression had significantly favorable prognoses for overall survival (P = 0.0026) and disease free survival (DFS; P = 0.0007) compared with the other groups. In particular, among patients with adenocarcinoma, similar results were even more significant. In multivariate analysis, immunohistochemical KAI1/CD82 expression in patients with NSCLC was an independent prognostic factor for overall survival and DFS; in those with adenocarcinoma, it was an even more valuable factor. In some patients with NSCLC, especially those with adenocarcinoma, KAI1/CD82 expression levels in metastatic lesions were diminished compared with levels of expression in the primary lung lesions.

CONCLUSIONS

The immunohistochemically determined level of KAI1/CD82 expression in NSCLC cells within tumor tissue appears to be a favorable prognostic factor for overall survival as well as DFS. The results of this study suggest that decreased KAI1/CD82 expression may be associated with tumor progression and enhanced metastatic potential in some patients with this disease. Cancer 1998;83:466-474. © 1998 American Cancer Society.

The KAI1 gene was first isolated from the human chromosome 11p11.2 in prostate carcinoma cells.1 CD82 was primarily identified by cDNA cloning as the R2 antigen in mitogen-activated human T cells and was subsequently cloned as IA4 and C33 antigens.2-5 The KAI1 gene product is identical to CD82, designated as KAI1/CD82, which is a representative member of the transmembrane-4 superfamily (TM4SF) of cell membrane glycoproteins containing a type III integral membrane structure with four transmembrane domains.6 This novel family has been shown to be widely distributed in some human nonhematopoietic cells, leukocytes, and neoplastic cells.7

It is noteworthy that, although the biophysiologic function of this superfamily remains unclear, it has been strongly suggested that alterations in expression of these cell membrane glycoproteins may be associated with tumor progression in some tumor cells. Indeed, prostate carcinomas with low levels of KAI1/CD82 gene expression have had more aggressive biologic characteristics than those with high levels,1, 8, 9 and similar observations have been noted for pancreatic,10 bladder,11 and breast carcinomas.12

Recently, we have examined KAI1/CD82 expression in nonsmall cell lung carcinoma (NSCLC) by the reverse transcriptase-polymerase chain reaction (RT-PCR) method, using KAI1/CD82 specific oligonucleotides, and we found that patients with a high level of KAI1 gene expression had better prognoses than those with a low level.13 However, in this preliminary study, these findings may reflect the total amounts of KAI1/CD82 within the tumor tissue, not KAI1/CD82 expression status in cancer cells, because stromal cells expressing KAI1/CD82 infiltrated the tissue. Furthermore, the value of KAI1/CD82 expression in predicting disease free survival (DFS), considered to be more important for determining its association with tumor malignancy, remains undetermined. Moreover, KAI1/CD82 expression status in metastatic lesions from NSCLC is unknown in comparison with that in primary lesions.

Therefore, to determine the possible inverse association of KAI1/CD82 expression and tumor progression purely by estimating its expression in lung carcinoma cells, we performed an immunohistochemical study using monoclonal antibody against the KAI1/CD82 gene product in tumor tissues from patients with this disease. In addition, its expression status in matched pairs of primary and metastatic lesions was comparatively analyzed.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Clinical Characteristics of Patients

We studied 200 patients with NSCLC who had undergone surgery at the Department of Thoracic Surgery of Osaka Medical Center for Cancer and Cardiovascular Diseases (formerly, the Center for Adult Diseases, Osaka) between March 1992 and December 1995. All patients underwent potentially curative surgery without preoperative or postoperative adjuvant therapy. Treatment was given only when the tumor recurred. The patients were 141 men and 59 women ages 35-83 years (mean age, 63.7 years; standard deviation, 9.7 years). According to the international TNM staging system,14 these cases comprised 95 patients with pathologic Stage I, 29 with pathologic Stage II, 58 with pathologic Stage IIIA, and 18 with pathologic Stage IIIB disease. The median postoperative follow-up for patients who had undergone potentially curative surgery was 795 days (range, 66-1839 days). DFS in the patients was estimated using the day of clinically initial recurrence. In some patients, in whom the tumor recurred in distant organs, tissue from metastatic lesions were surgically obtained.

Immunohistochemistry

Immunohistochemical staining using frozen sections of the patients' tumors was performed as described by Ueda et al., with minor modifications.8 The sections, fixed with 10% formalin for 5 minutes at 4°C, were immersed for 20 minutes in 0.3% H2O2 in absolute methanol, then treated with 5% normal horse serum. Incubation for 1 hour with the anti-KAI1/CD82 mouse monoclonal antibody, C33,3-5, 8 at a dilution of 1 : 500, was followed by incubation with biotinylated horse antimouse immunoglobulin (Ig)G (Vector, Burlingame, CA) and the avidine-biotin-peroxidase complex (Vectastain ABC kit, Vector). This C33 antibody was not cross-reactive against the other members of TM4SF.3-5 The peroxidase reaction used 3,3'-diaminobenzidine tetrahydrochloride in the presence of 0.05% H2O2. As the negative control, nonimmunized purified rat IgG2a was used instead of the C33 antibody. In all specimens, adjacent noncancerous pneumocytes were used as an internal positive controls for KAI1/CD82 expression.

Specimen Classification Based on Immunohistochemical Results

KAI1/CD82 was expressed primarily in the membranous portion of noncancerous cells, such as some infiltrating lymphocytes, fibroblasts, bronchial epithelia, and pneumocytes, as well as in that of cancer cells at various degrees of staining intensity. Similar immunostaining patterns had been observed in the prostate gland tissues, its neoplastic tissues,8 and some lymphocytes in previous studies.3-5 Therefore, the criteria of immunostaining positivity for KAI1/CD82 expression in cancer cells were based on staining intensity in comparison with that in adjacent normal pneumocytes; cancer cells with immunostaining intensity similar to or stronger than that in pneumocytes were judged as KAI1/CD82 positive, whereas those showing weaker or no immunostaining intensity were considered KAI1/CD82 negative.

When the percentage of KAI1/CD82 positive cancer cells within the tumor tissue was 50% or greater, the sample was classified as KAI1/CD82 positive; when 5% or more but less than 50%, as KAI1/CD82 reduced; and when 0% or less than 5%, as KAI1/CD82 negative (Fig. 1 (23K)). These judgments were carried out by three observers with mutual consent.

thumbnail image

Figure 1. Immunostaining of KAI1/CD82 expression in nonsmall cell lung carcinoma is shown (hematoxylin counterstaining, original magnification x40). (A) KAI1/CD82 expression was observed primarily in the membranous portion of almost all cancer cells within the tumor tissue (well-differentiated adenocarcinoma type is shown). (B) KAI1/CD82 expression was observed only in a minority of lung cancer cells (arrowhead), but a majority of cancer cells showed no expression of KAI1/CD82. Some stromal cells within the tumor tissue strongly showed its expression (moderately differentiated adenocarcinoma type is shown). (C) In contrast to some KAI1/CD82 positive adjacent normal alveolar cells (arrowhead), adenocarcinoma cells showed no expression of KAI1/CD82 (poorly differentiated adenocarcinoma type is shown).

Download figure to PowerPoint

Statistical Analysis

The chi-square test was used to compare the association between KAI1/CD82 expression level and clinicopathologic factors. The Kaplan-Meier method was used to calculate postoperative DFS or overall survival rate, and prognostic significance was evaluated by the log rank test. Multivariate analysis for prognostic value in DFS or overall survival were analyzed with the Cox proportional hazards regression model using SAS software (Cary, NC). P values <0.05 were considered significant.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Association of KAI1/CD82 Expression with Clinicopathologic Factors

Of the 200 patients with NSCLC in the current series, 104 (52%) were KAI1/CD82 negative, 31 (15.5%) were KAI1/CD82 reduced, and 65 (32.5%) showed immunohistochemical KAI1/CD82 positive expression.

Among these three groups, there was no significant association with patient age, histologic type, differentiation, T classification, lymph node involvement, stage, or tumor size (Table 1). The KAI1/CD82 expression level was slightly associated with gender (P = 0.058), but not significantly.

Table 1. Relation between Immunohistochemical KAI1/CD82 Expression and Clinicopathologic Factors in 200 NSCLC Patients
 All patients 200 (%)KAI1/CD82 statusP value
Negative 104 (52%)Reduced 31 (15.5%)Positive 65 (32.5%)
  1. NSCLC: nonsmall cell lung carcinoma; SD: standard deviation; NS: not significant; Ad: adenocarcinoma; Sq: squamous cell carcinoma; La: large cell carcinoma; As: adenosquamous cell carcinoma; Non-ad; Sq, La, and As.

Age (mean ± SD, yrs)63.7  ±  9.763.4 ± 9.564.3 ± 7.164.1 ± 11.0NS
Gender (male/female)141/5981/2319/1241/240.058
Histologya     
  Ad116572237 
  Sq6837823 
  La12813 
  As42020.271 (Ad vs. Non-adb)
Differentiation     
  Well4014917 
  Moderate97531529 
  Poor, Laa63377190.166
T classification     
  T15426820 
  T298531431 
  T3, T448259140.878
Lymph node involvement     
  N0121551947 
  N13922611 
  N2, N34027670.112
Stage     
  I95441437 
  II291748 
  IIIA, IIIB764313200.451
Tumor size (mm)     
  <3167301027 
  ≤31, <61106601828 
  ≤6127143100.375

Postoperative Survival Analysis

Postoperative overall survival curves, according to the immunohistochemical KAI1/CD82 expression level in 200 NSCLC patients, are shown in Figure 2A (7K). Patients with KAI1/CD82 positive expression had significantly more favorable prognoses than those with the other two groups (3-year survival rates: positive, 86%; reduced, 56%; negative, 66%; positive vs. reduced and negative, P = 0.0026). In particular, among 116 patients with adenocarcinoma, more significant results in the overall survival analysis were obtained (Fig. 2B (7K), 3 (7K)-year survival rates: positive, 95%; reduced, 65%; negative, 70%; positive vs. reduced and negative, P = 0.0010). There were no differences in prognosis between the KAI1/CD82 reduced and KAI1/CD82 negative groups. Figure 3 (7K) shows DFS curves of the KAI1/CD82 positive and the other two groups (Fig. 3A (7K), NSCLC; Fig. 3B (7K), adenocarcinoma). Patients with KAI1/CD82 positive expression also had significantly favorable prognoses (NSCLC, 3-year DFS rates: positive, 76% vs. reduced and negative, 48%, P = 0.0007; adenocarcinoma, 3-year DFS rates: positive, 78% vs. reduced and negative, 46%, P = 0.0005). In contrast, among patients with squamous cell carcinoma, there was no significant difference in overall survival and DFS according to KAI1/CD82 expression status (data not shown).

thumbnail image

Figure 2. Postoperative overall survival is shown, according to KAI1/CD82 expression status, for 200 nonsmall cell lung carcinoma (NSCLC) patients (A) and 116 adenocarcinoma patients (B) who underwent potentially curative surgery. NSCLC patients with KAI1/CD82 positive expression had a significantly more favorable prognosis than those with KAI1/CD82 reduced and negative expression (3-year survival rates: positive, 86%; reduced, 56%; negative, 66%; positive vs. reduced and negative, P = 0.0026). In particular, among patients with adenocarcinoma, this result in overall survival analysis was more significant (3-year survival rate: positive, 95%; reduced, 65%; negative, 70%; positive vs. reduced and negative, P = 0.0010).

Download figure to PowerPoint

thumbnail image

Figure 3. Postoperative disease free survival (DFS) according to KAI1/CD82 expression status in 200 nonsmall cell lung carcinoma (NSCLC) patients (A) and 116 adenocarcinoma patients (B) undergoing potentially curative surgery. NSCLC patients with KAI1/CD82 positive expression had a significantly more favorable prognosis than those of the other two groups. (3-year DFS rate: positive, 76% vs. reduced and negative, 48%; P = 0.0007). This finding was more prominent among the patients with adenocarcinoma (3-year DFS rate: positive, 78% vs. reduced and negative, 46%, P = 0.0005).

Download figure to PowerPoint

Table 2 summarizes a multivariate analysis of prognostic value in overall survival and DFS in 200 NSCLC patients. In the current series, a significant prognostic value in overall survival was observed in lymph node involvement (P = 0.001), KAI1/CD82 (P = 0.037), T classification (P = 0.041), and tumor size (P = 0.045), and a significant prognostic value in DFS was also observed in lymph node involvement (P = 0.0001) and KAI1/CD82 (P = 0.035). In multivariate analysis in patients with adenocarcinoma (Table 3), KAI1/CD82 expression status had independent prognostic value in overall survival (P = 0.041), second to lymph node involvement (P = 0.003); and in DFS it was also an independent prognostic factor (P = 0.013), second to lymph node involvement (P = 0.0001).

Table 2. Multivariate Analysis for Prognosis in 200 Patients with NSCLC
VariablesOverall survivalDisease free survival
Risk ratio95% CIP valueRisk ratio95% CIP value
  1. NSCLC: nonsmall cell lung carcinoma; CI: confidence interval; La: large cell carcinoma.

Age, yrs (≤64 vs. ≤65)1.0020.973-1.0330.8810.9930.969-1.0170.567
Gender (male vs. female)0.8190.403-1.6630.5811.1770.692-2.0000.548
Differentiation (well, moderate vs. poor, La)1.4790.948-2.3090.0871.4070.979-2.0220.066
T classification (T1, 2 vs. T3, 4)1.3611.014-1.8270.0411.2060.936-1.5540.148
Lymph node involvement (N0 vs. N1, 2, 3)1.6331.215-2.1950.0011.6731.304-2.1470.0001
Size (mm) (<35 vs. ≤35)1.9821.018-3.8560.0451.6800.997-2.8200.051
KAI1/CD82 (negative, reduced vs. positive)0.7000.502-0.9760.0370.7500.575-0.9770.035
Table 3. Multivariate Analysis for Prognosis in 116 Patients with Adenocarcinoma
VariablesOverall survivalDisease free survival
Risk ratio95% CIP valueRisk ratio95% CIP value
  1. CI: confidence interval.

Age, yrs (≤64 vs. ≤65)1.0090.971-1.0490.6360.9970.968-1.0270.853
Gender (male vs. female)0.5520.224-1.2130.1340.7180.386-1.3350.298
Differentiation (well, moderate vs. poor)2.0751.019-4.2230.0471.7351.083-2.7790.024
T classification (T1, 2 vs. T3)1.3940.908-2.1420.1320.7290.158-1.3310.436
Lymph node involvement (N0 vs. N1, 2, 3)2.0111.278-3.1630.0031.8781.342-2.6290.0001
Size (mm) (<35 vs. ≤35)2.5361.027-6.2620.0462.0391.062-3.9140.034
KAI1/CD82 (negative, reduced vs. positive)0.5670.331-0.9710.0410.6180.425-0.8970.013

Comparative Analysis of Immunohistochemical KAI1/CD82 Expression in Matched Pairs of Primary and Metastatic Lesions

The KAI1/CD82 expression status of 31 metastatic lesions from NSCLCs was immunohistochemically analyzed and compared with that in the paired primary lesions (Table 4). These samples (22 adenocarcinomas and 9 squamous cell carcinomas) were made up of 18 metastatic regional lymph nodes and 13 distant metastatic lesions (6 in the brain, 3 in the adrenal gland, 2 in the liver, and 2 in the lung). Overall, 11 patients showed a change in expression in metastatic lesions, compared with expression in the paired primary tumors (increased expression, 2 patients; decreased expression, 9 patients). In particular, of six patients with KAI1/CD82 positive expression in the primary lesion, four showed reduced expression in the metastatic lesion. Histologically, among 22 patients with adenocarcinoma, a total of 8 patients showed decreased expression in metastatic lesions in comparison with that in the paired primary lung tumors, although the others showed the same level of expression.

Table 4. Comparative Analysis of KAI1/CD82 Expression in Matched Pairs of Primary and Metastatic Lesions (Adenocarcinoma, n = 22; Squamous Cell Carcinoma, n = 9)
 Metastatic lesiona KAI1/CD82 expression
Positive n = 2 (1)Reduced n = 10 (6)Negative n = 19 (15)
  • ( ): No. of patients with adenocarcinoma.

  • a

    Regional lymph node (n = 18), brain (n = 6), adrenal gland (n = 3), liver (n = 2), lung (n = 2).

Primary lung lesion KAI1/CD82 expression   
    Positive n = 6 (4)2  (1)4  (3)0
    Reduced n = 9 (8)04  (3)5  (5)
    Negative n = 16 (10)02  (0)14  (10)

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Using the RT-PCR method, Adachi et al.13 demonstrated that a high level of KAI1/CD82 gene expression in NSCLC, especially lung adenocarcinoma, is a favorable prognostic factor. In the current immunohistochemical analysis of KAI1/CD82 expression, even solely in cancer cells (although there was no significant association between KAI1/CD82 expression status and clinicopathologic factors), patients with KAI1/CD82 positive expression in cancer cells had significantly good prognoses; these observations were particularly significant among those with adenocarcinoma. Thus, it appears that the findings in the current immunohistochemical study were almost in agreement with those shown by gene analysis using the RT-PCR method.13

Samples were grouped as positive, reduced, or negative, according to the percentage of immunohistochemically KAI1/CD82 positive cancer cells. However, there was no clinicopathologic or prognostic difference between samples from the reduced and negative groups. Therefore, based on an immunostaining cutoff point of 50%, it seemed appropriate to combine these two groups. With this cutoff point, the ratio of KAI1/CD82 positive expression to tested patients was close to that in the previous study, which used the RT-PCR method:13 32.5% in this study vs. 23.2% in RT-PCR analysis.

Preliminarily, in order to determine whether there was an association of KAI1/CD82 expression between immunohistochemistry and RT-PCR method, its expression status was comparatively analyzed in some patients who had been included in our previously reported series13 (data not shown). According to the McNemar test, there was no statistically significant difference between the current immunohistochemical data and the prior RT-PCR data, suggesting that there was a good correlation of these methods in the estimation of KAI1/CD82 expression in each NSCLC patient. However, a few patients with adenocarcinoma, regarded as KAI1/CD82 positive by RT-PCR, were included in the KAI1/CD82 reduced group by immunohistochemistry. Considering that the results obtained in RT-PCR analysis were based on total amounts of the KAI1/CD82 transcript level in the tissue, KAI1/CD82-expressing stromal cells and/or noncancerous epithelia components might strongly influence its expression status in the tissue in such patients. In contrast, there were also a few patients, mainly with nonadenocarcinoma type, who belonged to the reduced group according to RT-PCR but to the positive group according to immunohistochemistry. Intratumoral heterogeneity of KAI1/CD82 expression in the samples may have been strongly associated, but the reason for this is not clear. At any rate, by the current study, it was again demonstrated that these exceptions occurred only in a minority of patients.

In the current study, in univariate analysis using the log rank test, patients with positive expression of KAI1/CD82 had favorable prognoses for overall survival (P = 0.0026), and prognostic value was also observed in multivariate analysis (P = 0.035). Especially in patients with adenocarcinoma, these observations were more markedly observed (univariate analysis using the log rank test, P = 0.0010; multivariate analysis, P = 0.041). Moreover, in the current study, it was noted that immunohistochemical KAI1/CD82 expression status in NSCLCs, especially in adenocarcinomas, is also an independent prognostic marker for DFS (NSCLCs: univariate analysis using the log rank test, P = 0.0007; multivariate analysis, P = 0.035; adenocarcinomas: univariate analysis using the log rank test, P = 0.0005; multivariate analysis, P = 0.013). In determining the biologic characteristics of tumor malignancy accurately, DFS analysis is considered to be more important and preferable, because postoperative overall survival periods may be influenced by postrecurrent therapy. Therefore, immunohistochemical KAI1/CD82 expression status in NSCLC, particularly in lung adenocarcinoma, may be clinically useful for detecting a subgroup with a high risk of recurrence among postoperative patients. Our finding that the prognostic value of KAI1/CD82 expression status was second to that of lymph node involvement suggests that it is an indicator of strategy for the postoperative treatment of patients without lymph node involvement. Moreover, considering that immunohistochemistry is routinely and easily performed in comparison with the RT-PCR method, it appears that immunohistochemical KAI1/CD82 expression status in NSCLC is more available in clinical practice.

Besides KAI1/CD82, there are many representative members of the TM4SF, including motility-related protein (MRP-1)/CD9,15-19 CD37,20 CD53,21 ME491/CD63,22 TAPA-1/CD81,23 PETA3/CD151,24 CO-029,25 and Sm23,26 some of which have been shown to be inversely associated with tumor progression in several malignant tumors.17-19, 22 Indeed, we previously reported that reduced MRP-1/CD9 expression in NSCLCs, especially in lung adenocarcinoma,19 as well as in breast carcinoma is a useful unfavorable prognostic factor associated with tumor aggressiveness.18 Considering a possible biologic role of MRP1/CD9 as a regulator of cell motility,15, 16 these findings may be reasonable.

In contrast, the C33 antigen, i.e., KAI1/CD82 protein, was identified by monoclonal antibody, the C33 antibody used in the current study, was originally shown as inhibitory to syncytium formation induced by human T-cell leukemia virus type I,3-5 and this specific inhibition to syncytium formation induced by some human T-cell line by this antibody was strongly associated with altered glycosylation of cell surface antigen,3-5 suggesting that the C33 antigen, i.e., KAI1/CD82 protein, might play a possible role in cell-to-cell adhesion mechanism. Recently, it was also reported that some breast carcinoma cell lines with highly metastatic propensity and invasive ability showed lower levels of KAI1 mRNA.12 These results suggest that this gene product might be a metastasis-suppressor or a less aggressive associated glycoprotein.

In this respect, in addition to the favorable prognostic significance of KAI1/CD82 protein expression, it was also noted that in a few patients, especially those with lung adenocarcinoma, the degree of its expression in metastatic lesions was decreased in comparison with that in the matched primary lesions. Regarding MRP1/CD9 expression, this similar observation was also previously observed in breast carcinoma.18 Therefore, in NSCLCs, especially adenocarcinomas, the possibility exists that decreased KAI1/CD82 expression may be associated with enhanced metastatic potential. Conversely, it is speculated that KAI1/CD82 protein may be, in part, functionally related to the metastasis-inhibiting activity.

However, in the current study, there was no association between KAI1/CD82 expression and prognostic value in patients with histologically nonadenocarcinoma type, mainly squamous cell carcinoma of the lung. Interestingly, we previously noted that the prognostic value of MRP-1/CD9 expression in tumor cells may vary depending on tissue and/or histologic type.19 Therefore, the role of KAI1/CD82 protein in inhibiting metastasis of NSCLCs, if any, may be limited and complicated, and may vary depending on the specificity of tissue and/or the histologic type.1 In fact, it was experimentally shown that the introduction of chromosome 11, containing KAI1/CD82 gene, into highly metastatic rat mammary tumor cells had no effect on metastatic potential.27 Thus, the precise mechanism of the inverse effect of KAI1/CD82 expression in NSCLCs (especially adenocarcinoma cells) on tumor progression, namely, the reason why its expression status in these diseases is a favorable prognostic factor, is not yet known. Further attempts to determine the role of TM4SF, including KAI1/CD82 and MRP-1/CD9, in patients with NSCLC are needed.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

The authors thank Mrs. Y. Funai and Mrs. Y. Koyanagi for technical assistance.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  • 1
    Dong J-T, Lamb PW, Rinker-Schaeffer CW, Yukanovic J, Ichikawa T, Isaacs JT, et al. KAI-1, a metastatic suppressor gene for prostatic cancer on human chromosome 11p11.2. Science 1995; 268: 884-6.
  • 2
    Gaugitsch HW, Hofer E, Huber NE, Schnabl E, Baumruker T. A new superfamily of lymphoid and melanoma cell proteins with extensive homology to Schitosoma mansoni antigen Sm23. Eur J Immunol 1991; 21: 377-83.
  • 3
    Fukudome K, Furuse M, Imai T, Nishimura M, Takagi S, Hinuma Y, et al. Identification of membrane antigen C33 recognized by monoclonal antibodies inhibitory to human T-cell leukemia virus type 1 (HTLV-1)-induced syncytium formation: altered glycosylation of C33 antigen in HTLV-1-positive cells. J Virol 1992; 66: 1394-401.
  • 4
    Imai T, Fukudome K, Takagi S, Nagira M, Furuse M, Fukuhara N, et al. C33 antigen recognized by monoclonal antibodies inhibitory to human T cell leukemia virus type 1-induced syncytium formation is a member of a new family of transmembrane proteins including CD9, CD37, CD53, and CD63. J Immunol 1992; 149: 2879-86.
  • 5
    Imai T, Yoshie O. C33 antigen and M38 antigen recognized by monoclonal antibodies inhibitory to syncytium formation by human T cell leukemia virus type 1 are both members of the transmembrane 4 superfamily and associate with each other and with CD4 or CD8 in T cells. J Immunol 1993; 151: 6470-81.
  • 6
    Wright MD, Tomlinson MG. The ins and outs of the transmembrane-4 superfamily. Immunol Today 1995; 15: 588-94.
  • 7
    Horejsi V, Vlcek C. Novel structurally distinct family of leukocyte surface glycoproteins including CD9, CD37, CD53, and CD63. FEBS Lett 1991; 288: 1-4.
  • 8
    Ueda T, Ichikawa T, Tamaru J, Mikata A, Akakura K, Akimoto S, et al. Expression of the KAI1 protein in benign prostatic hyperplasia and prostate cancer. Am J Pathol 1996; 149: 1435-40.
  • 9
    Dong J-T, Suzuki H, Pin SS, Bova GS, Schalken JA, Isaacs WB, et al. Down-regulation of the KAI1 metastasis suppressor gene during the progression of human prostatic cancer infrequently involves gene mutation or allelic loss. Cancer Res 1996; 56: 4387-90.
  • 10
    Guo X, Friess H, Graber HU, Kashiwagi M, Zimmermann A, Kore M, et al. KAI1 expression id up-regulated in early pancreatic cancer and decreased in the presence of metastases. Cancer Res 1996; 56: 4876-80.
  • 11
    Yu Y, Yang J-L, Markovic B, Jackson P, Yardley G, Barrett J, et al. Loss of KAI1 messenger RNA expression in both high-grade and invasive human bladder cancers. Clin Cancer Res 1997; 3: 1056-9.
  • 12
    Yang X, Welch DR, Phillips KK, Weissman BE, Wei LL, KAI1, a putative marker for metastatic potential in human breast cancer. Cancer Lett 1997; 119: 149-55 .
  • 13
    Adachi M, Taki T, Ieki Y, Huang C-L, Higashiyama M, Miyake M. Correlation of KAI1/CD82 gene expression with good prognosis of patients with non-small cell lung cancer. Cancer Res 1996; 56: 1751-5.
  • 14
    American Joint Committee on Cancer, BeahrsOH, HensonDE, HutterRVP, KennedyBJ, editors. Manual for Staging of Cancer, 4th edition. Philadelphia: J.B. Lippincott, 1992: 115-22.
  • 15
    Miyake M, Koyama M, Seno M, Ikeyama S. Identification of the motility-related protein (MRP-1), recognized by monoclonal antibody M31-15, which inhibits cell motility. J Exp Med 1991; 174: 1347-54.
  • 16
    Ikeyama S, Koyama M, Yamaoko M, Sasada R, Miyake M. Suppression of cell motility and metastasis by transfection with human motility-related protein (MRP-1/CD9) DNA. J Exp Med 1993; 177: 1231-7.
  • 17
    Si Z, Hersey P. Expression of the neuroglandular antigen and analogues in melanoma. CD9 expression appears inversely related to metastatic potential of melanoma. Int J Cancer 1993; 54: 37-43.
  • 18
    Miyake M, Nakano K, Ieki Y, Adachi M, Hunang C-L, Itoi S, et al. Motility related protein-1 (MRP-1/CD9) expression: inverse correlation with metastases in breast cancer. Cancer Res 1995; 55: 4127-31.
  • 19
    Higashiyama M, Taki T, Adachi M, Huang C-L, Koh T, Kodama K, et al. Reduced-motility-related protein-1 (MRP-1/CD9) gene expression as a factor of poor prognosis in non-small cell lung cancer. Cancer Res 1995; 55: 6040-4.
  • 20
    Classon BJ, Williams AF, Willis AC, Seed B, Stamenkovic I. The primary structure of the human leukocyte antigen CD37, a species homologue of the rat MRC OX-44 antigen. J Exp Med 1989; 169: 1497-502.
  • 21
    Amiot M. Identification and analysis of cDNA clones encoding CD53: a pan-leukocyte antigen related to membrane transport proteins. J Immunol 1990; 145: 4322-5.
  • 22
    Hotta H, Ross AH, Huebner K, Isobe M, Wendeborn S, Chao MV, et al. Molecular cloning and characterization of an antigen associated with early stages of melanoma tumor progression. Cancer Res 1988; 48: 2955-62.
  • 23
    Oren R, Takahashi S, Doss C, Levy R, Levy S. TAPA-1, the target of an antiproliferative antibody, defines a new family of transmembrane proteins. Mol Cell Biol 1990; 10: 4007-15.
  • 24
    Sincock PM, Mayrhofer G, Ashman LK. Localization of the transmembrane 4 superfamily (TM4SF) member PETA-3 (CD151) in normal human tissue: comparison with CD9, CD63, and ∂5β1 integrin. J Histochem Cytochem 1997; 45: 515-25.
  • 25
    Szala S, Kasai Y, Steplewski Z, Rodeck U, Koprowski H, Linnenbach AJ. Molecular cloning of cDNA for the human tumor-associated antigen CO-029 and identification of related transmembrane antigen. Proc Natl Acad Sci U S A 1990; 87: 6833-7.
  • 26
    Wright MD, Henkle KJ, Mitchell GF. An immunogenic Mr-23,000 integral membrane protein of Schistosoma mansoni worms that closely resembles a human tumor-associated antigen. J Immunol 1990; 144: 3195-200.
  • 27
    Rinker-Schaeffer CW, Hawkins AL, Ru N, Dong J, Stoica G, Griffin CA, et al. Differential suppression of mammary and prostate cancer metastasis by human chromosomes 17 and 11. Cancer Res 1994; 54: 6249-56.