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Combined status of MUC1 mucin and surfactant apoprotein A expression can predict the outcome of patients with small-size lung adenocarcinoma.
Tsutsumida H, Goto M, Kitajima S, Kubota I, Hirotsu Y, Yonezawa S.
Division of Human Pathology, Department of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences and 1Department of Surgery, National Minamikyushu Hospital, Kagoshima, Japan.
AIM: : Lung cancer is still a disease of high mortality, despite advanced diagnostic techniques. Here, we aim to report a unique method to predict the recurrence and outcome of patients with pulmonary adenocarcinomas. METHODS AND RESULTS: : Immunohistochemical expression of MUC1 mucin and surfactant apoprotein A (SP-A) was examined in 185 cases of surgically removed lung adenocarcinomas of non-bronchioloalveolar type smaller than 30 mm. Staining results were evaluated semiquantitatively, and the expression of MUC1 and SP-A was compared in each case. There were 140/185 (76%) cases showing MUC1 expression higher than SP-A expression (MUC1>SP-A), and 45/185 (24%) cases showing MUC1 expression lower than or equal to SP-A expression (MUC1</=SP-A). Recurrence was observed in 24% (34/140) of the patients with a MUC1>SP-A pattern, but in 7% (3/45) of the patients with a MUC1</=SP-A pattern after the median observation period of 41 months (1-99 months) (P < 0.01). The MUC1>SP-A group showed higher recurrence and worse survival than the MUC1</=SP-A group by Kaplan-Meier's method (P < 0.01 and P < 0.005). Even in the patients with apparently favourable prognostic factors (well-differentiated adenocarcinoma or no lymph node metastasis), recurrence and survival were different between the two groups. CONCLUSIONS: : A high MUC1/SP-A ratio is strongly associated with a poor outcome in patients with small-size lung adenocarcinoma.
Clin Lung Cancer. 2001 Aug;3(1):49-57; discussion 58.
Phase I study of the BLP25 (MUC1 peptide) liposomal vaccine for active specific immunotherapy in stage IIIB/IV non-small-cell lung cancer.
Palmer M, Parker J, Modi S, Butts C, Smylie M, Meikle A, Kehoe M, MacLean G, Longenecker M.
Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada. martinp@cancerboard.ab.ca
Active specific immunotherapy with liposomal vaccines targeted to the mucinous carcinoma-associated glycoprotein MUC1 have shown promising results in animal models. The aim of this phase I study was to evaluate the safety and immunogenicity of 2 dose levels of the MUC1 liposomal vaccine preparation BLP25. Patients with stage IIIB or IV non-small-cell lung cancer received either 20 microg or 200 microg of the liposomal BLP25 vaccine preparation. Injections were administered subcutaneously at weeks 0, 2, 5, and 9. Immunological responses to vaccination were measured by antibody production, cytotoxic T lymphocytes (CTL), and proliferative T-helper cells. Seventeen patients were entered on study; 12 patients completed the vaccination protocol. Two patients, 1 in each dose group, developed clinically insignificant grade 3 lymphopenia during the study. Nonhematologic toxicities were mild and self-limiting, and there were no significant long-term injection site reactions. Immunological assays revealed the generation of CTLs against MUC1-positive tumor cell lines in 5 of 12 evaluable patients. These patients did not have CTLs prior to receiving the vaccine. No significant humoral response to the vaccination was observed. No objective antitumor responses were observed. Of the 12 patients completing all the vaccinations, 4 had stable disease. Median survival time was 5.4 months in the 20 microg group and 14.6 months in the 200 microg group. In summary, the BLP25 liposomal vaccine was well tolerated and elicited a primarily cellular immune response in these lung cancer patients. This study forms the basis for further clinical exploration of the MUC1 liposomal vaccine, BLP25.
Int J Mol Med. 2003 Oct;12(4):493-502. Related Articles, Links
Dendritic cell vaccine immunotherapy of cancer targeting MUC1 mucin.
Kontani K, Taguchi O, Ozaki Y, Hanaoka J, Sawai S, Inoue S, Abe H, Hanasawa K, Fujino S.
Department of Surgery, Shiga University of Medical Science, Seta, Otsu 520-2192, Japan. konbat@belle.shiga-med.ac.jp
The use of dendritic cells (DCs) for cancer vaccination is effective in suppressing cancer progression. This is because the DCs play a crucial role in priming tumor-specific immunity efficiently as antigen-presenting cells. In this study, we analyzed the ability of DCs to elicit tumor-specific immunity and clinical effects of DC vaccine immunotherapy targeting MUC1 tumor antigens. DCs from 14 patients with advanced or metastatic breast or lung cancer (9 positive for MUC1 and 5 negative for MUC1) were loaded with MUC1 antigens or tumor lysate and used for therapeutic vaccination. After vaccination, all the MUC1-positive patients acquired antigen-specific immunity whereas only 1 case with MUC1-negative cancer showed the specific immunity. Clinically, marked effects such as reduction in tumor sizes or tumor marker levels or disappearance of malignant pleural effusion were observed in 7 of the 9 MUC1-positive cases. However, MUC1-negative patients did not respond to DC vaccines, with the exception of 1 case with MAGE3-positive lung cancer. Survival of MUC1-positive patients was significantly prolonged in comparison with MUC1-negative patients (mean survival: 16.75 versus 3.80 months, p=0.0101). These data suggest that MUC1 is sufficiently immunogenic to elicit strong anti-tumor immunity as a tumor antigen and that DC vaccines targeting MUC1 are useful for immunotherapy of cancer.
Lung Cancer. 2003 Aug;41 Suppl 1:S103-13.
Lung cancer vaccines and gene therapy.
Hege KM, Carbone DP.
Cell Genesys, Inc., 500 Forbes Blvd., South San Francisco, CA 94080, USA. kristen.hege@cellgenesys.com
A number of cancer vaccine and gene therapy approaches are being evaluated in patients with lung cancer. Cancer vaccine strategies include GM-CSF gene-modified cancer cells, liposomal MUC1 peptide, anti-idiotype antibody targeting GD3, Mage-3 peptide, and mutant p53 pulsed dendritic cells among others. Preliminary human trials have demonstrated immune responses as well as tumor regression in late stage disease. The largest human gene therapy experience in lung cancer is with intratumoral gene replacement therapy, predominantly with p53, but such approaches are limited to locoregional disease control. Earlier stage gene therapy programs targeting the immune system or tumor vasculature hold promise as systemic therapies for treatment of advanced, disseminated disease.
Normal respiratory mucosa, precursor lesions and lung carcinomas: differential expression of human mucin genes.
Copin MC, Buisine MP, Devisme L, Leroy X, Escande F, Gosselin B, Aubert JP, Porchet N.
Laboratoire de Biochimie et Biologie Moleculaire, Hopital C. Huriez. CHRU Lille, France, Faculte de Medecine, Universite de Lille II, Lille, France. mccopin@chru-lille.fr
Mucins are glycoproteins synthesized by epithelial cells and thought to promote tumor-cell invasion. Eight human mucin genes have been well characterized: MUC2, MUC5AC, MUC5B, MUC6 map to 11p15.5 and encode secretory gel forming mucins while MUC1, MUC3, MUC4, MUC7 are scattered on different chromosomes and encode membrane-bound or secreted mucins. The expression pattern of the mucin genes is complex in normal airways involving six genes, mainly MUC5AC and MUC5B in mucus-producing cells and MUC4 in a wide array of epithelial cells. MUC5AC overexpression in metaplasia, dysplasia and normal epithelium adjacent to squamous cell carcinoma provides additional arguments for a mucous cell origin of preneoplastic squamous lesions. MUC5AC and MUC5B expression is related to mucus formation in adenocarcinomas. Mucinous bronchioloalveolar carcinoma (BAC) has a particular pattern of mucin gene expression indicating that it has sustained a well-differentiated phenotype similar to the goblet cell, correlated with distinctive features i.e. a noninvasive pattern and a better prognosis than nonBACs. MUC4 is the earlier mucin gene expressed in the foregut, before epithelial differentiation and is expressed independently of mucus secretion both in normal adult airways and carcinomas. These findings are in favor the histogenetic theory of non-small-cell carcinoma originating from a pluripotent mucous cell.
Membrane-bound (MUC1) and secretory (MUC2, MUC3, and MUC4) mucin gene expression in human lung cancer.
Nguyen PL, Niehans GA, Cherwitz DL, Kim YS, Ho SB.
Department of Medicine, VA Medical Center, Minneapolis, MN 55417, USA.
Abnormalities of mucin-type glycoproteins have been described in lung cancers, but their molecular basis is unknown. In this study, mucin-core-peptide-specific antibodies and cDNA probes were used to determine the relative expression of mucin genes corresponding to one membrane-bound mucin (MUC1), two intestinal mucins (MUC2 and MUC3), and one tracheobronchial mucin (MUC4) in normal (nonneoplastic) lung, and in lung neoplasms. Normal lung tissues exhibited a distinct pattern of mucin gene expression, with high levels of MUC1 and MUC4 mRNA and low to absent levels of MUC2 and MUC3 mucin immunoreactivity and mRNA. In contrast, lung adenocarcinomas, especially well-differentiated cancers, exhibited increased MUC1, MUC3, and MUC4 mRNA levels. Lung squamous-cell, adenosquamous, and large-cell carcinomas were characterized by increased levels of MUC4 mucin only. We conclude that the expression of one membrane-bound and several secretory-type mucins is independently regulated and markedly altered in lung neoplasms. The frequent occurrence of increased MUC4 transcripts in a variety of non-small-cell lung cancers indicates the potential importance of this type of mucin in lung cancer biology.
Pattern of mucin gene expression in normal and neoplastic lung tissues.
Seregni E, Botti C, Lombardo C, Cantoni A, Bogni A, Cataldo I, Bombardieri E.
Nuclear Medicine Department, Istituto Nazionale Tumori, Milano, Italy.
This work evaluates the expression in lung cancer of the most well characterized mucin genes (MUC1, MUC2, MUC3) and of the recently described MUC4 in lung tissues, to check a correlation between the expression of any particular gene and this tumor. Hybridization with synthetic oligonucleotides obtained from a part of the sequences of MUC1, MUC2, MUC3 and MUC4, was performed on blotted RNA from 18 lung cancer tissue specimens and from 10 normal tissues samples taken, when possible, from the normal lung counterpart. By means of Northern blot analysis MUC1 revealed to be the most expressed mucin gene in lung cancer, followed by MUC4; by contrast, the expression of MUC2 and MUC3 was almost undetectable in all cancer specimens. The intensity of expression of MUC1 and MUC4 was always superior in cancer tissue than in the normal counterpart. As expected, the highest reactivity for MUC1 and MUC4 expression was observed mainly in the adenocarcinoma histotype which is mucin secreting. These findings represent a contribution to the study of mucin gene pattern in lung cancer, and, in particular, indicate that MUC4, in association with the MUC1 gene, seems to be strongly expressed in this neoplastic disease.