Original Article
Correlation of Expression of H/LeY/LeB Antigens with Survival in Patients with Carcinoma of the Lung
N Engl J Med 1992; 327:14-18July 2, 1992
- Abstract
- Abstract
Background.
The level of expression of H/Ley/Leb antigens is high in various histologic types of lung cancer, a feature that may be related to deletion of A and B blood-group antigens. We evaluated the possibility that expression of this antigen, which can be defined by the monoclonal antibody MIA-15–5, might be of prognostic value, as suggested by our previous observation that MIA-15–5 inhibits tumor-cell motility and metastasis.
Methods.
We used MIA-15–5 to stain tissue sections from 149 patients with primary lung cancer whose clinicopathological histories were well documented. The survival curves for patients whose tumors stained positively were compared with the curves for those whose tumors stained negatively. Multivariate analyses were performed with a Cox proportional-hazards regression model.
Results.
Among the 149 patients studied, five-year survival in the 91 patients with MIA-positive tumors was significantly lower than survival in the 58 with MIA-negative tumors (20.9 percent vs. 58.6 percent, P<0.001). Among the 67 patients with squamous-cell carcinoma, the rates also differed significantly (10.5 percent vs. 62.1 percent, P<0.001). The difference in survival between patients with MIA-positive tumors and those with MIA-negative tumors was significant among patients with blood groups A and AB (P<0.001), but not among those with blood group B or O (P = 0.071 and 0.068, respectively). Multivariate analysis with the Cox regression model indicated that positivity best correlated with five-year mortality, followed by lymph-node status (N stage) and tumor size (T stage), whereas sex, age, and blood group did not correlate with mortality.
Conclusions.
Positivity for MIA (i.e., immunohistologic staining by MIA-15–5, which defines H/Ley/Leb antigens) is inversely correlated with survival among patients with primary lung cancer and may be of prognostic value. (N Engl J Med 1992;327:14–8.)
Media in This Article
Figure 1
Survival in 149 Patients with Lung Cancer, According to Expression of MIA Antigen in Tumor.Figure 2
Survival in 131 Patients with Squamous-Cell Carcinoma or Adenocarcinoma, According to MIA-Antigen Status.Article Activity
- Article
THE observation that various human cancers frequently lose blood-group A and B determinants was originally made by Masamune and associates in immunochemical studies1 , 2 and by Davidsohn and associates in studies of immunofluorescence reactions and immunoadhesion of A or B erythrocytes on histologic sections.3 4 5 In association with the loss of A or B antigens, the expression of their precursor, antigen H, and H-related antigens increased.2 , 6 In normal cells and tissues the expression of H-related structures is much greater in O cells than in A or B cells,7 but in cancerous cells enhanced expression of H-related structures is independent of the host's blood group (ABO status) and is due to other mechanisms in addition to deletion of A or B antigens. Such deletion may occur before the tumor develops and may be a sign of precancer8; it may also be of prognostic value, since it is more pronounced in malignant cells with greater potential for invasion.9 10 11 Recently, Lee et al.12 observed that the expression of A antigen in patients with lung cancer correlated with survival: the average survival of those with blood group A or AB whose primary tumors were negative for A antigen was significantly less than that of those whose tumors showed continuous expression of A antigen. Disease progressed more rapidly in the patients with A-negative tumors than in those with tumors that remained A-positive.12
We recently developed two monoclonal antibodies that inhibit the motility and metastatic potential of tumor cells (MIA-15–5 and MIA-22–20; MIA denotes migration-inhibitory antibody, defined by the MIA antigen). Both antibodies inhibited tumor-cell motility and were directed to a common carbohydrate structure, Fucα1→2Galβ1→R (in which R denotes either type 1 or type 2 chain with or without internal fucosylation — i.e., H/Ley/Leb). The antigenic affinity and motility-inhibiting activity of MIA-15–5 were stronger than those of MIA-22–20. Other anti-H antibodies, whose specificities may have been restricted by the structure of their carrier carbohydrate, did not inhibit cell motility or metastasis, perhaps because of lower affinity for the structure of the respective H antigen or H-related antigen.13 Tumor cells expressing the monoclonal antibody MIA-15–5—defined antigen (hereafter termed "MIA antigen") have a higher degree of cell motility and invasiveness than tumor cells not expressing this antigen.13
Because of the possibility that the positivity of a lung carcinoma for MIA might likewise define its invasiveness and metastatic potential, we retrospectively evaluated the expression of MIA antigen in tumor tissue from 149 patients with lung cancer for whom adequate clinicopathological information was available.
Methods
Clinical Characteristics of the Patients
All the patients we studied underwent surgery between March 1978 and April 1983 at the Department of Thoracic Surgery, Chest Disease Research Institute, Kyoto University, Kyoto, Japan. Their clinical records and histopathological diagnosis were fully documented. Tumor samples were preserved as formalin-fixed, paraffin-embedded sections. The blood group (A, B, O, or AB status) of each patient was determined and recorded at the time of surgery. The postsurgical pathological stage of each tumor was classified according to the tumor—node—metastasis (TNM) system14 — that is, by its pathological classification (stage I, II, or IIIA disease), presence and degree of lymph-node metastasis (N0, N1, or N2), and tumor size (T1, T2, or T3).
Since a large number of ill-defined factors are involved in late-stage lung cancer (stages IIIB and IV — i.e., with a status worse than N3 and T4), the effect of a single factor such as MIA positivity could be considerably diluted and obscured. Furthermore, because the five-year survival rate for patients with stage IIIB disease and N3 metastasis is known to range from 0 to 5 percent, we considered survival analysis of such patients pointless in the context of the present study and therefore excluded 52 patients with stage IIIB or IV disease. Because the average life spans of Japanese men and women are 78 and 81 years, respectively, we studied only patients 32 to 73 years of age, thus excluding 10 patients more than 74 years of age. We also excluded the following patients: 26 patients receiving preoperative chemotherapy or radiation; 5 patients who died of complications after surgery ("operative death"); 6 patients with two or more forms of cancer; and 3 patients who died as a result of traffic accidents or had a major disease other than cancer (i.e., diabetes). In summary, we studied 149 patients 32 to 73 years old with disease up to stage IIIA (i.e., up to N2 and T3) from among 251 patients initially considered.
Histopathological and Immunohistologic Examination
The lung tumors were classified histologically according to the criteria of the World Health Organization.15 Formalin-fixed, paraffin-embedded tumor samples from the primary tumor were examined immunohistologically with the avidin–biotin complex technique, as follows. Tumor sections (4 μm thick) were soaked in xylene to remove paraffin and dehydrated in graded ethanol. Endogenous peroxidase activity was blocked by treatment of the sections with 0.3 percent hydrogen peroxide for 20 minutes. The sections were washed in 50 mM TRIS buffer (pH 7.4) for five minutes, incubated with normal goat serum for two hours at room temperature, and exposed overnight to monoclonal antibody MIA-15–5 (concentration, 10 μg per milliliter). Next, they were washed in 50 mM TRIS buffer for 20 minutes, treated with biotinylated goat antimouse IgM solution for 2 hours, washed for 20 minutes, and treated with phosphate-buffered saline containing the avidin–biotin complex for 1 hour. Finally, they were washed in 50 mM TRIS buffer for 30 minutes, incubated with substrate solution containing 3′,3′-diaminobenzidine for 1 minute, washed with water, and weakly counterstained with hematoxylin. Sections incubated with mouse IgM were used as negative controls.
Biotinylated goat antimouse IgM, avidin, and biotin were purchased from Vectastain (Burlingame, Calif.). Staining was defined as positive if the membranes or cytoplasm of more than 5 percent of the tumor cells stained. In the majority of positive cases, more than 30 percent of the tumor-cell population was stained. All slides were analyzed without knowledge of the clinical information about the patients.
Statistical Analysis
Survival curves were computed according to the method of Kaplan and Meier,16 and differences in survival between subgroups of patients were compared with Mantel's log-rank test.17 Survival was measured in days, beginning with the day of surgery. The Cox proportional-hazards regression model18 was used to study the effects of different variables on survival. Six factors (sex, age, blood group, T stage, N stage, and MIA status of the tumor) were studied; scores were assigned to each variable for the regression analysis.
Results
Survival and Expression of MIA Antigen
Clinical Variables
Expression of the MIA antigen in all tumors studied did not differ significantly among subgroups defined by age, sex, or other clinicopathological variables (Table 1Table 1
Survival of 149 Patients with Lung Cancer, According to Clinicopathological Characteristics and Status for MIA Antigen.). However, comparison of five-year survival among all 149 patients according to the expression of MIA antigen showed that the average survival of MIA-positive patients was lower than that of MIA-negative patients (Table 1 and Fig. 1Figure 1Survival in 149 Patients with Lung Cancer, According to Expression of MIA Antigen in Tumor.). Overall, the five-year survival rate of the 91 patients with MIA-positive tumors was 20.9 percent, and that of the 58 patients with MIA-negative tumors was 58.6 percent (P<0.001).Histologic Variables and Blood Group
Expression of the MIA antigen was essentially similar in the four subgroups defined by the histologic types of lung cancer. In the subgroup with squamous-cell carcinoma, the five-year survival rate was 10.5 percent in patients whose tumors stained positively for MIA and 62.1 percent in those whose tumors stained negatively (P<0.001) (Table 1). In contrast, in the subgroup with adenocarcinoma, the rates associated with positive and negative staining were 36.6 percent and 60.9 percent, respectively (P = 0.015). Although the subgroup with large-cell carcinoma was small, the survival rates associated with positive and negative staining differed significantly — 0 percent as compared with 66.7 percent (P = 0.020). Ten-year survival curves for the subgroups with squamous-cell carcinoma and adenocarcinoma are shown in Figure 2Figure 2
Survival in 131 Patients with Squamous-Cell Carcinoma or Adenocarcinoma, According to MIA-Antigen Status..Because the MIA antigen is the precursor of A and B blood-group antigens,13 and deletion of the A antigen correlates with survival among patients with lung cancer,12 we examined survival rates as a function of MIA-antigen expression and blood group (A, B, O, or AB). Differences in survival between patients with the MIA antigen and those without it were significant in the subgroups with blood groups A (P<0.001) and AB (P = 0.003); the differences approached significance in the subgroups with blood group O (P = 0.068) and B (P = 0.071) (Table 1). The difference between the survival curves for MIA-positive and MIA-negative patients with blood group A (i.e., both those with group A and those with group AB) and corresponding curves for patients with blood group B or O were significant (data not shown). However, blood-group status did not correlate with the Kaplan–Meier survival curve (data not shown); this finding was supported by Cox regression analysis, which indicated that blood group, in contrast to nodal status and tumor stage, did not correlate with survival.
Prognostic Value of MIA Status
The variables used in the Cox regression analysis are shown in Table 2Table 2
Value of Six Variables in Predicting Survival of 149 Patients with Lung Cancer, According to Cox Regression Analysis.; the estimated prognostic value of each variable in relation to overall survival among the 149 patients studied is expressed as a P value. Three variables (MIA status, N stage, and T stage) were found to be significant in the prediction of survival; MIA status had the lowest P value (P<0.001). Blood group, age, and sex were not significant predictors of survival (P>0.1). Other variables studied (for example, the serum concentrations of lactate dehydrogenase, albumin, and carcinoembryonic antigen) had no relation to MIA status or its prognostic value (data not shown).Discussion
Aberrant glycosylation is common in essentially all animal and human cancers, regardless of their causal agent, "oncogene" activation, or histopathological type.19 Since the majority of human tumors arise from endodermal epithelia where concentrations of blood-group antigens are high, changes in blood-group ABH antigens and Lewis-related antigens are among the most common alterations. Enhanced synthesis of fucosylated or sialylated lacto-series type 1 or type 2 chain structures (e.g., H/Ley/Leb, Lea, Lex, sialosyl-Lea, and sialosyl-Lex) is most common in various human cancers derived from endodermal epithelia and is ascribable to unrestricted fucosylation or sialylation. Enhanced expression of H/Ley/Leb in tumors is due partially to inhibition of A and B glycosyltransferases,20 but is also dependent on other factors — such as status as a secretor or nonsecretor of A and B antigens, status for Lewis blood groups, unrestricted α1→3/4 fucosylation, and MIA negativity caused by sialylation of type 1 or type 2 chain.
Davidsohn et al. reported that A-antigen and B-antigen determinants are lost in all anaplastic tumors3 but retained in differentiated tumors and benign adenomas. This was first observed in gastrointestinal tumors and subsequently in cancers of the ovary, skin, tongue, larynx, bladder, and cervix.4 , 5 H-antigen—related structures were not known at the time of these studies and could not be investigated.
Recently, Lee et al. observed that the survival of patients with lung cancer who had deletion of A antigen is much less than that of patients with continued expression of this antigen.12 The correlation of A-antigen deletion with survival was stronger in patients with stage I tumors than in those with stage II or III tumors. The correlation of B-antigen deletion with survival in patients with blood group B was weaker than that of A-antigen deletion.12
Using monoclonal antibody MIA-15–5, we previously demonstrated inhibition of the motility and metastatic potential of tumor cells expressing the MIA antigen. This antibody was able to recognize H-related antigen regardless of the structure of the carrier carbohydrate (i.e., H/Ley/Leb). Although the basis of inhibition of tumor-cell motility by MIA-15–5 is still unknown, sections from 45 to 65 percent of human lung cancers (regardless of histologic type) stained with this monoclonal antibody, a phenomenon that we found to be inversely correlated with survival among patients with lung cancer. Thus, expression of the MIA antigen may be associated with metastatic and invasive properties of lung-tumor cells.
In the present study, Cox multivariate regression analysis showed that positive status for MIA was the strongest predictor of survival. N stage and T stage also significantly correlated with survival, but age, blood group, and sex did not. We did not use the Cox model to analyze survival in relation to the histologic type of the tumor, but the Kaplan–Meier survival curve and the correlation of survival with positive status for MIA among the patients with squamous-cell carcinoma were clearly different from the corresponding values in patients with adenocarcinoma. Since lung adenocarcinoma expresses various other carbohydrate antigens in high levels,21 , 22 the effect of MIA antigen could be diluted or obscured in this disease. The negative correlation of positivity for MIA with survival was stronger among patients with blood group A than among those with group O or B, but blood group was not strongly predictive of survival.
How does expression of H-related antigens lead to malignancy in a tumor? A few possibilities can be considered. First, the potential of tumor cells for invasion and metastasis is closely associated with motility, which apparently depends on specific glycosylation (e.g., by MIA antigen) and which appears to be highly dependent on the presence of a receptor that controls a cell-motility factor.23 A 78-kd glycoprotein receptor specific for an autocrine factor that strongly promotes cell motility24 appears to be glycosylated by MIA antigen (H/Ley/Leb) (unpublished data). Cell motility may be promoted if this receptor or others are glycosylated by the H/Ley/Leb structure, whereas cell motility is inhibited when the receptors bear the A or B determinant. Second, the MIA antigen could be an adhesion molecule that is selectively bound to lectins expressed at the defined target cell (e.g., the specific region of endothelium). Third, H/Ley/Leb epitopes are recognized by complementary carbohydrates expressed at specific regions of endothelium or organs (unpublished data).
In patients with colon cancer, expression of the sialosyl-Tn or sialosyl-Lex antigen has prognostic value. In a study of 128 primary colorectal carcinomas, the six-year survival rate was 100 percent in patients without the sialosyl-Tn antigen and 68 percent in those with the antigen.25 Similarly, the survival rate was 55 percent in patients whose tumors showed low levels of expression of sialosyl-Lex and 15 percent in those whose tumors had high levels (unpublished data; see Fig. 2 of Hakomori26). These findings suggest that tumor-associated carbohydrate antigens have an important functional role in defining the invasiveness and potential for metastasis of human cancers.26 Glycosylation patterns of tumors induced in animals differ from those of human cancers, but many reports support a functional role of cell-surface carbohydrates in experimental metastasis.27 Studies of the pathobiologic importance of tumor-associated carbohydrate antigens may reveal tools for predicting and controlling the progression of human cancer.
Supported by a grant from the Osaka Lung Cancer Study Group, an award from the Japan Lung Cancer Society (to Dr. Miyake), an Outstanding Investigator Grant (CA-42505 [to Dr. Hakomori]) from the National Cancer Institute, and funds from the Biomembrane Institute.
We are indebted to Dr. Stephen Anderson for scientific editing and preparation of the manuscript.
Source Information
From the Department of Thoracic Surgery, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan (M.M., T.T.); the Department of Thoracic Surgery, Chest Disease Research Institute, Kyoto University, Kyoto, Japan (S. Hitomi); and the Biomembrane Institute and the Department of Pathobiology, University of Washington, Seattle (S. Hakomori). Address reprint requests to Dr. Miyake at Kitano Hospital, Kita-Kie, Osaka 530, Japan.
- References
References
1
Masamune
CrossRef | Medline2
Masamune
CrossRef | Medline3
Davidsohn
Web of Science | Medline4
Kovarik
Web of Science | Medline5
Davidsohn
Web of Science | Medline6
Dabelsteen
Web of Science | Medline7
Hakomori S, Kobata A. Blood group antigens. In: Sela M, ed. The antigens. Vol. 2. New York: Academic Press, 1974:79–140.
8
Dabelsteen
Medline9
Kay
Web of Science | Medline10
Coon
CrossRef | Web of Science | Medline11
Orntoft
CrossRef | Web of Science | Medline12
Lee
Full Text | Web of Science | Medline13
Miyake
CrossRef | Web of Science | Medline14
Hermanek P, Sobin LH, eds. TNM classification of malignant tumours. 4th ed. Berlin, Germany: Springer-Verlag, 1987:69–73.
15
The World Health Organization histological typing of lung tumours: second edition . Am J Clin Pathol 1982;77:123–36.
Web of Science | Medline16
Kaplan
CrossRef | Web of Science17
Mantel
Medline18
Cox 19
Hakomori
CrossRef | Web of Science | Medline20
Stellner
CrossRef | Web of Science | Medline21
Miyake
Web of Science | Medline22
Itai
Web of Science | Medline23
Rosen
CrossRef | Web of Science | Medline24
Silletti
Web of Science | Medline25
Itzkowitz
CrossRef | Web of Science | Medline26
Hakomori
CrossRef | Web of Science | Medline27
Stanford
CrossRef | Web of Science | Medline
- Citing Articles (76)
Citing Articles
1
Elizabeth L Bird-Lieberman, André A Neves, Pierre Lao-Sirieix, Maria O'Donovan, Marco Novelli, Laurence B Lovat, William S Eng, Lara K Mahal, Kevin M Brindle, Rebecca C Fitzgerald. (2012) Molecular imaging using fluorescent lectins permits rapid endoscopic identification of dysplasia in Barrett's esophagus. Nature Medicine
CrossRef2
Seigo Kashimura, Zenichiro Saze, Masanori Terashima, Nobutoshi Soeta, Satoshi Ohtani, Fumihiko Osuka, Michihiko Kogure, Mitsukazu Gotoh. (2011) CD83+ dendritic cells and Foxp3+ regulatory T cells in primary lesions and regional lymph nodes are inversely correlated with prognosis of gastric cancer. Gastric Cancer
CrossRef3
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CrossRef4
Li-Mei Yan, Bei Lin, Lian-Cheng Zhu, Ying-Ying Hao, Yue Qi, Chang-Zhi Wang, Song Gao, Shui-Ce Liu, Shu-Lan Zhang, Masao Iwamori. (2010) Enhancement of the adhesive and spreading potentials of ovarian carcinoma RMG-1 cells due to increased expression of integrin α5β1 with the Lewis Y-structure on transfection of the α1,2-fucosyltransferase gene. Biochimie 92:7, 852-857
CrossRef5
S Peinert, H M Prince, P M Guru, M H Kershaw, M J Smyth, J A Trapani, P Gambell, S Harrison, A M Scott, F E Smyth, P K Darcy, K Tainton, P Neeson, D S Ritchie, D Hönemann. (2010) Gene-modified T cells as immunotherapy for multiple myeloma and acute myeloid leukemia expressing the Lewis Y antigen. Gene Therapy 17:5, 678-686
CrossRef6
Munetoyo Toda, Hiroshi Nakada. (2010) Immunosuppressive Effect of Carcinoma-Produced Mucins on B Cell Function. Trends in Glycoscience and Glycotechnology 22:127, 226-238
CrossRef7
Jennifer A. Westwood, William K. Murray, Melanie Trivett, Nicole M. Haynes, Benjamin Solomon, Linda Mileshkin, David Ball, Michael Michael, Angela Burman, Preethi Mayura-Guru, Joseph A. Trapani, Stefan Peinert, Dirk Hönemann, H. Miles Prince, Andrew M. Scott, Mark J. Smyth, Phillip K. Darcy, Michael H. Kershaw. (2009) The Lewis-Y Carbohydrate Antigen is Expressed by Many Human Tumors and Can Serve as a Target for Genetically Redirected T cells Despite the Presence of Soluble Antigen in Serum. Journal of Immunotherapy 32:3, 292-301
CrossRef8
S. Hatakeyama, K. Sugihara, J. Nakayama, T. O. Akama, S.-M. A. Wong, H. Kawashima, J. Zhang, D. F. Smith, C. Ohyama, M. Fukuda, M. N. Fukuda. (2009) Identification of mRNA splicing factors as the endothelial receptor for carbohydrate-dependent lung colonization of cancer cells. Proceedings of the National Academy of Sciences 106:9, 3095-3100
CrossRef9
Ying-Ying Li, Ling-Ling Hsieh, Rei-Ping Tang, Shuen-Keui Liao, Kun-Yun Yeh. (2009) Macrophage-derived interleukin-6 up-regulates MUC1, but down-regulates MUC2 expression in the human colon cancer HT-29 cell line. Cellular Immunology 256:1-2, 19-26
CrossRef10
Emilio Quaia, Lee M. Krug, Neeta Pandit-Taskar, Andrew Nagel, Victor E. Reuter, John Humm, Chaitanya Divgi. (2008) The value of gamma camera and computed tomography data set coregistration to assess Lewis Y antigen targeting in small cell lung cancer by 111Indium-labeled humanized monoclonal antibody 3S193. European Journal of Radiology 67:2, 292-299
CrossRef11
Munetoyo Toda, Kaoru Akita, Mizue Inoue, Shigeru Taketani, Hiroshi Nakada. (2008) Down-modulation of B cell signal transduction by ligation of mucins to CD22. Biochemical and Biophysical Research Communications 372:1, 45-50
CrossRef12
Zhenbo Zhang, Ping Sun, Jiwei Liu, Li Fu, Jie Yan, Yuejian Liu, Lihua Yu, Xiaoqi Wang, Qiu Yan. (2008) Suppression of FUT1/FUT4 expression by siRNA inhibits tumor growth. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1783:2, 287-296
CrossRef13
Manfred Schuster, Wolfgang Jost, Geert C. Mudde, Susanne Wiederkum, Cornelia Schwager, Evelyne Janzek, Friedrich Altmann, Johannes Stadlmann, Christian Stemmer, Gilbert Gorr. (2007) In vivo glyco-engineered antibody with improved lytic potential produced by an innovative non-mammalian expression system. Biotechnology Journal 2:6, 700-708
CrossRef14
Kousaku Mimura, Koji Kono, Akihiro Takahashi, Yoshihiko Kawaguchi, Hideki Fujii. (2007) Vascular endothelial growth factor inhibits the function of human mature dendritic cells mediated by VEGF receptor-2. Cancer Immunology, Immunotherapy 56:6, 761-770
CrossRef15
Kousaku Mimura, Koji Kono, Akihiro Takahashi, Yoshihiko Kawaguchi, Yoshiki Mizukami, Hideki Fujii. (2007) Vascular Endothelial Growth Factor Partially Inhibits the Trastuzumab-Mediated Antibody-Dependent Cellular Cytotoxicity of Human Monocytes. Oncology 72:3-4, 172-180
CrossRef16
Norio Yokoigawa, Noriko Takeuchi, Munetoyo Toda, Mizue Inoue, Masaki Kaibori, Hidesuke Yanagida, Takaaki Inaba, Hironori Tanaka, Tokuhiro Ogura, Hideho Takada, Tadayoshi Okumura, A-Hon Kwon, Yasuo Kamiyama, Hiroshi Nakada. (2007) Overproduction of PGE2 in peripheral blood monocytes of gastrointestinal cancer patients with mucins in their bloodstream. Cancer Letters 245:1-2, 149-155
CrossRef17
Danielle H. Dube, Carolyn R. Bertozzi. (2005) Glycans in cancer and inflammation — potential for therapeutics and diagnostics. Nature Reviews Drug Discovery 4:6, 477-488
CrossRef18
Hidemitsu Sugai, Koji Kono, Akihiro Takahashi, Fumiko Ichihara, Hiromitsu Kawaida, Hideki Fujii, Yoshiro Matsumoto. (2004) Characteristic alteration of monocytes with increased intracellular IL-10 and IL-12 in patients with advanced-stage gastric cancer. Journal of Surgical Research 116:2, 277-287
CrossRef19
Ching-Chiang Yang, Kang-Chu Chu, Wen-Meng Yeh. (2004) The expression of vascular endothelial growth factor in transitional cell carcinoma of urinary bladder is correlated with cancer progression. Urologic Oncology: Seminars and Original Investigations 22:1, 1-6
CrossRef20
D. J. Becker. (2003) Fucose: biosynthesis and biological function in mammals. Glycobiology 13:7, 41R-53
CrossRef21
Christine L Lau, Mary-Beth H Moore, Kelly R Brooks, Thomas A D'Amico, David H Harpole. (2002) Molecular staging of lung and esophageal cancer. Surgical Clinics of North America 82:3, 497-523
CrossRef22
Erik Dabelsteen. (2002) ABO blood group antigens in oral mucosa. What is new?. Journal of Oral Pathology & Medicine 31:2, 65-70
CrossRef23
Samuel B. Ho, Young S. Kim. 2002. Glycoproteins and Glycosylation Changes in Cancer. , 309-324.
CrossRef24
E.V. Chandrasekaran. (2001) Human lung adenocarcinoma alpha1,3/4-L-fucosyltransferase displays two molecular forms, high substrate affinity for clustered sialyl LacNAc type 1 units as well as mucin core 2 sialyl LacNAc type 2 unit and novel alpha1,2-L-fucosylating activity. Glycobiology 11:5, 353-363
CrossRef25
JACQUES PENDU, SÉVERINE MARIONNEAU, ANNE CAILLEAU-THOMAS, JÉZABEL ROCHER, BÉATRICE MOULLAC-VAIDYE, MONIQUE CLÉMENT. (2001) ABH and Lewis histo-blood group antigens in cancer. APMIS 109:1, 9-26
CrossRef26
I Brockhausen. (1999) Pathways of O-glycan biosynthesis in cancer cells. Biochimica et Biophysica Acta (BBA) - General Subjects 1473:1, 67-95
CrossRef27
Xin Xie, Morten Boysen, Ole Petter F. Clausen, Magne A. Bryne. (1999) Prognostic Value of Le y and H Antigens in Oral Tongue Carcinomas. The Laryngoscope 109:9, 1474-1480
CrossRef28
Torben F. Orntoft, Else Marie Vestergaard. (1999) Clinical aspects of altered glycosylation of glycoproteins in cancer. Electrophoresis 20:2, 362-371
CrossRef29
Maria V Croce, Andrea G Colussi, MG DE Bravo, Michel R Price, Amanda Segal-Eiras. (1998) Immunohistopathological characterization of spontaneous metastases in a human lung mucoepidermoid adenocarcinoma (HLMC) Xenograft. Pathology & Oncology Research 4:4, 259-266
CrossRef30
Fumihiro Tanaka, Ryo Miyahara, Yohsuke Ohtake, Kazuhiro Yanagihara, Tatsuo Fukuse, Shigeki Hitomi, Hiromi Wada. (1998) Lewis Y antigen expression and postoperative survival in non–small cell lung cancer. The Annals of Thoracic Surgery 66:5, 1745-1750
CrossRef31
Tohru Nakagoe, Kiyoyasu Fukushima, Takashi Tuji, Terumitu Sawai, Atushi Nanashima, Hiroyuki Yamaguchi, Tohru Yasutake, Shinsuke Hara, Hiroyoshi Ayabe, Tatuki Matuo, Shimeru Kamihira. (1998) Immunohistochemical Expression of ABH/Lewis-Related Antigens in Primary Breast Carcinomas and Metastatic Lymph Node Lesions. Cancer Detection <html_ent glyph="@amp;" ascii="&"/> Prevention 22:6, 499-505
CrossRef32
Erik Dabelsteen, Birgitte Grøn, Ulla Mandel, Ian Mackenzie. (1998) Altered Expression of Epithelial Cell Surface Glycoconjugates and Intermediate Filaments at the Margins of Mucosal Wounds. Journal of Investigative Dermatology 111:4, 592-597
CrossRef33
O. Galanina, F. Hallouin, C. Goupille, N. Bovin, J. Le Pendu. (1998) Detection of a potential receptor for the H-blood-group antigen on rat colon-carcinoma cells and normal tissues. International Journal of Cancer 76:1, 136-140
CrossRef34
BORLAND, ROSS, GUY. (1998) Forms and functions of CD44. Immunology 93:2, 139-148
CrossRef35
Steve Silletti, Sandor Paku, Avraham Raz. (1997) Tumor cell motility and metastasis. Pathology & Oncology Research 3:3, 230-254
CrossRef36
Seiichi Saito, Seiichi Orikasa, Makoto Satoh, Chikara Ohyama, Akihiro Ito, Toshiko Takahashi. (1997) Expression of Globo-series Gangliosides in Human Renal Cell Carcinoma. Cancer Science 88:7, 652-659
CrossRef37
Trond Jorgensen, Yogesan Kanagasingam, Olav Kaalhus, Kjell J. Tveter, Magne Bryne, Fredrik Skjorten, Aasmund Berner, Havard E. Danielsen. (1997) Prognostic Factors in Patients With Metastatic (Stage D2) Prostate Cancer: Experience from the Scandinavian Prostatic Cancer Group Study-2. The Journal of Urology 158:1, 164-170
CrossRef38
Rafael Rosell, Alex Pifarré, Mariano Monzó, Julio Astudillo, M. Paz López-Cabrerizo, Roser Calvo, Isabel Moreno, Montserrat Sánchez-Céspedes, Albert Font, José J. Navas-Palacios. (1997) Reduced survival in patients with stage-I non-small-cell lung cancer associated with DNA-replication errors. International Journal of Cancer 74:3, 330-334
CrossRef39
David H. Johnson. (1997) Adjuvant chemotherapy for non-small cell lung cancer. Lung Cancer 17, S103-S110
CrossRef40
VIBEKE RAVN SKOVLUND. (1997) ABH and related histo-blood group antigens in normal & malignant human endometrium in relation to genetic and hormonal factors. APMIS 105:S69, 5-33
CrossRef41
Stephen L. Graziano. (1997) Non-small cell lung cancer: clinical value of new biological predictors. Lung Cancer 17, S37-S58
CrossRef42
Gary M. Strauss. (1997) PROGNOSTIC MARKERS IN RESECTABLE NON–SMALL CELL LUNG CANCER. Hematology/Oncology Clinics of North America 11:3, 409-434
CrossRef43
Shoji Nakamori, Masao Kameyama, Shingi Imaoka, Hiroshi Furukawa, Osamu Ishikawa, Yo Sasaki, Yuki Izumi, Tatsuro Irimura. (1997) Involvement of carbohydrate antigen sialyl Lewisx in colorectal cancer metastasis. Diseases of the Colon & Rectum 40:4, 420-431
CrossRef44
Hans-Joachim Gabius. (1997) Concepts of Tumor Lectinology. Cancer Investigation 15:5, 454-464
CrossRef45
Yoshifumi Matsushita, Suguru Yonezawa, Shoji Nakamori, Tatsuro Irimura, Eiichi Sato. (1997) Carbohydrate antigens aberrantly expressed in colorectal carcinoma. Critical Reviews in Oncology/Hematology 25:1, 27-54
CrossRef46
ERIK DABELSTEEN. (1996) REVIEW ARTICLE. CELL SURFACE CARBOHYDRATES AS PROGNOSTIC MARKERS IN HUMAN CARCINOMAS. The Journal of Pathology 179:4, 358-369
CrossRef47
Elizabeth Rosvold. (1996) Prognostic factors for patients with non-small cell lung cancer. Current Problems in Cancer 20:4, 272-279
CrossRef48
Peter Jackson. (1996) The analysis of fluorophore-labeled carbohydrates by polyacrylamide gel electrophoresis. Molecular Biotechnology 5:2, 101-123
CrossRef49
Kiyoshi Maeda, Yong-suk Chung, Yoshinari Ogawa, Soon-Myoung Kang, Masafumi Ogawa, Tetsuji Sawada, Michio Sowa. (1996) Prognostic value of vascular endothelial growth factor expression in gastric carcinoma. Cancer 77:5, 858-863
CrossRef50
Jon H Ritter, Carolyn M Dresler, Mark R Wick. (1995) Expression of bcl-2 protein in stage T1NOMO non-small cell lung carcinoma. Human Pathology 26:11, 1227-1232
CrossRef51
Chikara Ohyama, Seiichi Orikasa, Sadafumi Kawamura, Makoto Satoh, Seiichi Saito, Yasuo Fukushi, Steven B. Levery, Sen-Itiroh Hakomori. (1995) Galactosylgloboside expression in seminoma. Inverse correlation with metastatic potential. Cancer 76:6, 1043-1050
CrossRef52
Susan A. Brooks, Anthony J. C. Leathem. (1995) Expression of the CD15 antigen (Lewis x) in breast cancer. The Histochemical Journal 27:9, 689-693
CrossRef53
Jeremy R. Johnson, William G. Hammond, John R. Benfield, Henry Tesluk. (1995) Successful xenotransplantation of human lung cancer correlates with the metastatic phenotype. The Annals of Thoracic Surgery 60:1, 32-37
CrossRef54
Carolyn M. Dresler, Jon H. Ritter, Mark R. Wick, Charles L. Roper, G. Alexander Patterson, Joel D. Cooper. (1995) Immunostains for blood group antigens lack prognostic significance in T1 lung carcinoma. The Annals of Thoracic Surgery 59:5, 1069-1073
CrossRef55
Giorgio Vittorio Sotti, Paolo Masiero, Ernesto Pozzi. (1995) Biological prognostic factors in non-small cell lung cancer. Lung Cancer 12, S13-S25
CrossRef56
W.K. Evans. (1995) Adjuvant chemotherapy: results and perspectives. Lung Cancer 12, S35-S45
CrossRef57
Nico van Zandwijk, Wolter J. Mooi, Sjoerd Rodenhuis. (1995) Prognostic factors in NSCLC. Recent experiences. Lung Cancer 12, S27-S33
CrossRef58
E. Espinosa, J. Feliu, P. Zamora, M.González Barón, J.J. Sánchez, A. Ordónez, J. Espinosa. (1995) Serum albumin and other prognostic factors related to response and survival in patients with advanced non-small cell lung cancer. Lung Cancer 12:1-2, 67-76
CrossRef59
Jun-ichi Ogawa, Akemi Sano, Hiroshi Inoue, Shirosaku Koide. (1995) Expression of Lewis-related antigen and prognosis in stage I non—small cell lung cancer. The Annals of Thoracic Surgery 59:2, 412-415
CrossRef60
Jean-Blaise Wasserfallen, Peter Spaeth, Louis Guillou, Alain R. Pécoud. (1995) Acquired deficiency in C1-inhibitor associated with signet ring cell gastric adenocarcinoma: A probable connection of antitumor-associated antibodies, hemolytic anemia, and complement turnover. Journal of Allergy and Clinical Immunology 95:1, 124-131
CrossRef61
J.B. Sørensen. (1994) Impact of prognostic factors on endpoints for clinical studies. Lung Cancer 11, S45-S54
CrossRef62
R. Feld, M. Borges, V. Giner, R. Ginsberg, P. Harper, J. Klastersky, L. Lacquet, M. Paesmans, D. Payne, R. Rossell, W. Sause, J.P. Sculier, E. Shaw, J.B. Sorensen, T. Splinter, R. Stahel, P. Bunn. (1994) Prognostic factors in non-small cell lung cancer. Lung Cancer 11, S19-S23
CrossRef63
Toshiaki Kawai, Minoru Suzuki, Suminori Kono, Nariyoshi Shinomiya, Makoto Rokutanda, Keigo Takagi, Toshiro Ogata, Seiichi Tamai. (1994) Proliferating cell nuclear antigen and Ki-67 in lung carcinoma. Correlation with DNA flow cytometric analysis. Cancer 74:9, 2468-2475
CrossRef64
Rolf A. Stahel. (1994) Antigens, receptors and dominant oncogenes and the prognosis of non-small cell lung cancer. Lung Cancer 11, S31-S38
CrossRef65
Shoji Nakamori, Hideomi Watanabe, Masao Kameyama, Shingi Imaoka, Hiroshi Furukawa, Osamu Ishikawa, Yo Sasaki, Toshiyuki Kabuto, Avraham Raz. (1994) Expression of autocrine motility factor receptor in colorectal cancer as a predictor for disease recurrence. Cancer 74:7, 1855-1862
CrossRef66
Jill M. Siegfried, Autumn L.Gaither Davis, Joseph R. Testa, Jay D. Hunt, Robert J. Keenan, Samuel A. Yousem, Pamela S. Ritter, Peter F. Person, Rodney J. Landreneau. (1994) Ability to culture resectable non-small cell lung carcinomas is correlated with recurrence. The Annals of Thoracic Surgery 58:3, 662-667
CrossRef67
John L. Gwin, Andres J. P. Klein-Szanto, Shi-Yu Zhang, Pasha Agarwal, Andre Rogatko, Steven M. Keller. (1994) Loss of blood group antigen a in non-small cell lung cancer. Annals of Surgical Oncology 1:5, 423-427
CrossRef68
Magne Bryne, Erik Dabelsteen, Jahn M. Nesland. (1994) Type 2 chain glycosylation in thyroid carcinomas. Glycosylation & Disease 1:2, 119-125
CrossRef69
Jun-Ichi Ogawa, Toyohiko Tsurumi, Shunsuke Yamada, Shirosaku Koide, Akira Shohtsu. (1994) Blood vessel invasion and expression of sialyl lewisx and proliferating cell nuclear antigen in stage I non-small cell lung cancer. Relation to postoperative recurrence. Cancer 73:4, 1177-1183
CrossRef70
Hironobu Hamada, Nobuoki Kohno, Kunio Hiwada. (1994) A New Serum Tumor Marker, CAM 123-6, Highly Specific to Pulmonary Adenocarcinoma. Cancer Science 85:2, 211-219
CrossRef71
Peter Jackson, Malcolm G. Pluskal, William Skea. (1994) The use of polyacrylamide gel electrophoresis for the analysis of acidic glycans labeled with the fluorophore 2-aminoacridone. Electrophoresis 15:1, 896-902
CrossRef72
Pezzella, FrancescoTurley, HelenKuzu, IsinzuTungekar, Mohammed FahimDunnill, Michael S.Pierce, Chris B.Harris, AdrianGatter, Kevin C.Mason, David Y.. (1993) bcl-2 Protein in Non-Small-Cell Lung Carcinoma. New England Journal of Medicine 329:10, 690-694
Full Text73
Toshiaki Kawai, Minoru Suzuki, Katsuichi Kase, Yuichi Ozeki. (1993) Expression of carbohydrate antigens in human pulmonary adenocarcinoma. Cancer 72:5, 1581-1587
CrossRef74
Tatsuhiko Narita, Hiroomi Funahashi, Yasuyuki Satoh, Tadashi Watanabe, Hiroshi Takagi, Junichi Sakamoto. (1993) Association of expression of blood group-related carbohydrate antigens with prognosis in breast cancer. Cancer 71:10, 3044-3053
CrossRef75
(1992) Prediction of Survival in Lung Cancer. New England Journal of Medicine 327:22, 1597-1598
Full Text76
Lee, Jin S., Hong, Waun K., . (1992) Prognostic Factors in Lung Cancer. New England Journal of Medicine 327:1, 47-48
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- Glossary
Abbreviations Used
-
H antigen:
An antigen with the chemical structure Fucα1→2Galβ1→R, in which R is the carrier carbohydrate.
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Leb antigen:
An antigen with the chemical structure Fucα1→2Galβ1→ 3[Fucα1→4]GlcNAcβ1→R
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Ley antigen:
An antigen with the chemical structure Fucα1→2Galβ1→ 4[Fucα1→3]GlcNAcβ1→R
-
MIA:
Migration-inhibiting antibody
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MIA antigen:
An antigen defined by the migration-inhibitory antibody — i.e., the H-related antigen complex defined by the monoclonal antibody MIA-15–5.
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- Letters
