Original contributionExpression profile analysis in multiple human tumors identifies L1 (CD171) as a molecular marker for differential diagnosis and targeted therapy☆
Introduction
Despite considerable diagnostic and therapeutic achievements in the treatment of human carcinomas, there is still urgent need for better molecular tumor markers. Carcinomas often reexpress molecules involved in tissue morphogenesis and fetal development that are silenced in adult tissues. Such molecules could represent novel markers with the potential to be tumor targets for antibody-based therapy and serve for improved diagnostics.
The L1 adhesion molecule is a 200- to 220-kd type I membrane glycoprotein of the immunoglobulin super family, consisting of 6 immunoglobulin-like domains and 5 fibronectin type III repeats followed by a transmembrane region and a highly conserved cytoplasmic tail [1]. In neuronal cells, L1 is involved in morphogenic events, such as neuron-neuron adhesion, neurite fasciculation, synaptogenesis, neurite outgrowth on Schwann cells, and neuronal cell migration (for review, see Refs. [2], [3]). L1 is also involved in the branching of renal tubules during kidney development [4]. Low levels of L1 are expressed in hematopoietic cells [5], [6].
Several studies have previously investigated L1 expression in tumors using established cell lines, and fresh frozen or fixed paraffin-embedded tissues. L1 was found in lung cancer cell lines [7], gliomas [8], melanomas [9], [10], renal carcinoma [11], [12], ovarian and endometrial carcinomas [13], and colon carcinoma [14]. In melanoma [9], [10] and in ovarian/endometrial carcinoma [13], the presence of L1 was found to be associated with poor patient prognosis. Similar results have recently been shown for gastrointestinal (GI) stromal tumors [14]. In colon carcinoma, overexpression of L1 has been linked to aberrant β-catenin/T-cell factor signaling [15].
Our recent studies have shown that L1 might be a valuable new target for tumor therapy. We found that L1 monoclonal antibodies (mAbs) could block the proliferation of tumor cells in vitro and in vivo [16]. Anti-L1 mAb administration was capable of reducing tumor load and ascites formation from SKOV3 cells in NOD/Scid mice [16]. Before applying for clinical testing, a detailed analysis of L1 expression in tumors and normal tissues is urgently needed. Such an analysis was hampered by the lack of appropriate antibodies working in paraffin-embedded tissues. The availability of mAb L1-11A and the newly produced L1-specific mAb L1-14.10 has solved these technical problems. The present study provides a comprehensive analysis of L1 expression in normal adult and in a broad range of benign and malignant tumors.
Section snippets
Cells and antibodies
The breast cancer cell lines MCF7 and MDA-MB 435S were obtained from the tumor bank of DKFZ (Heidelberg, Germany). The human renal carcinoma cell lines Caki-1 and Foehn were derived from Ilse Novak-Hofer (PSI, Villingen, Switzerland). The ovarian carcinoma cell lines OVM and SKOV3 as well as CHO cells stably transfected with human L1 were described before [13]. All cells were cultivated in Dulbecco's Modified Eagle's Medium supplemented with 10% fetal calf serum at 37°C, 5% CO2, and 100%
Characterization of L1-specific mAbs
Using immunization with a recombinant L1-Fc fusion protein, we generated the novel L1 mAb L1-14.10. The mAb was specific for L1 as revealed by fluorescent staining (Fig. 1A) and Western blot analysis (Fig. 1B). Monoclonal antibody L1-14.10 was superior to the established mAb L1-11A in immunohistochemistry on paraffin sections, resulting in a more intense staining (Fig. 1C). The staining pattern of both mAbs was otherwise identical. Data presented in this study were obtained with both antibodies.
Discussion
L1 is a novel marker protein for ovarian and endometrial carcinomas with the potential to serve as a therapeutic target [16]. In the present study, we carried out a survey in human carcinomas and adult normal tissue to broaden our knowledge on the expression of L1. Our results show that L1 expression in tumors is restricted and not ubiquitous. Whereas expression in melanomas can be expected because of the neuroendocrine origin of these tumors, the expression in gynecological tumors is possibly
Acknowledgements
We thank Ludmila Braginsky for her skillful technical assistance, Brigitte Engelhardt for competent help with the artwork, and Dr Michael Sanderson for helpful comments on the manuscript.
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This work was supported by grant 10-2024-Al4 (P. A.) from the Deutsche Krebshilfe and a guest scientist stipend from DKFZ (M. F.).