CORRESPONDENCE

Re: Leptin—A Growth Factor in Normal and Malignant Breast Cells and for Normal Mammary Gland Development

Elisabeth Oelmann, Susan Haghgu, Emma Kulimova, Hubert Serve, Christiane Schmitmann, Wolfgang E. Berdel

Affiliations of authors: Department of Medicine, Hematology and Oncology, University Hospital, Westfaelische Wilhelms Universitaet Muenster, Germany,

Correspondence to: Wolfgang E. Berdel, MD, Department of Medicine, Hematology and Oncology, University Hospital, Westfaelische Wilhelms Universitaet Muenster, Albert Schweitzer St. 33, D-48149 Muenster, Germany (e-mail: berdel{at}uni-muenster.de).

Leptin is an endogenous protein important for the control of body weight and body fat. Further, obesity is a risk factor for breast cancer in postmenopausal women. In a recent issue of the journal, Cleary and colleagues (1) reported the presence of OB-Rb, the signaling long form of the leptin receptor, on two breast cell lines including T-47D, the leptin stimulation of anchorage-dependent and -independent growth of T-47D cells, and some related intracellular signaling events. Additionally, these authors cited various other reports on the presence of OB-Rb on human tumor cell types derived from carcinomas and leukemias. Although the observations reported are specific and well-documented, they may leave the impression that leptin might be a general inducer of tumor cell growth, which would greatly hamper its clinical utility.

We studied the expression of transcripts for human leptin, OB-Rb, and OB-Ra (short, non-signaling form of the leptin receptor) in human malignant cell lines of different histologic origin (Table 1Go). We found wide expression of leptin, OB-Rb, and OB-Ra transcripts by reverse transcription–polymerase chain reaction (RT–PCR; primer sequences available from the authors on request) as described (2,3). We also studied the influence of recombinant human leptin on anchorage-independent colony growth of 25 malignant human cell lines in methylcellulose–agar mixtures as described (24). We used such an assay because its in vitro results strongly predict the in vivo tumorigenicity of a given cell type (5,6) and the in vivo growth-modulating effects of cytokines (4). This type of assay also is used to predict clinical responsiveness of human tumors to cytotoxic drugs, with excellent in vitro-to-in vivo predictability (7). Thus, this assay appears to have high clinical relevance. We have detected no growth-stimulatory activity with leptin at 1–100 ng/mL in any of the cell lines tested including two breast cell lines HTB 26 and HTB 131 (see Table 1Go). In fact, clonal growth of the two breast cancer cell lines was slightly inhibited by leptin. This observation was independent of the expression of transcripts for leptin or its receptors in the cells. For the cell lines with mismatched receptor mRNA expression and biologic resistance, mechanisms such as posttranscriptional regulation, interference of ligand-receptor interaction by decoy binding proteins, receptor mutation, competitive binding to short forms of the receptor with no signaling, regulation of signaling, or autocrine production of leptin by the cells can be envisaged.


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Table 1. Colony formation of human tumor cell lines under the influence of recombinant human leptin and expression of transcripts for leptin receptors OB-Rb and OB-Ra and leptin
 
In conclusion, leptin receptors are expressed on a wide range of tumor cells and leptin might have tissue-specific effects on the phenotype of normal and malignant cells, including growth modulation [for references, see (1)]. However, our results indicate that stimulation of anchorage-independent colony growth even of receptor-bearing human tumor cells by leptin is largely absent. This information is important for the potential clinical use of leptin.

NOTES

We thank Amgen-Germany for supporting this work. S. Haghgu has contributed experiments in partial fulfillment of the requirements for the MD thesis of the Westfaelische Wilhelms Universitaet Muenster. E. Kulimova is supported by a fellowship from the European Society for Medical Oncology.

REFERENCES

1 Hu X, Juneja SC, Maihle NJ, Cleary MP. Leptin—a growth factor in normal and malignant breast cells and for normal mammary gland development. J Natl Cancer Inst 2002;94:1704–11.[Abstract/Free Full Text]

2 Oelmann E, Kraemer A, Serve H, Reufi B, Oberberg D, Patt S, et al. Autocrine interleukin-1 receptor antagonist can support malignant growth of glioblastoma by blocking growth-inhibiting autocrine loop of interleukin-1. Int J Cancer 1997;71:1066–76.[CrossRef][ISI][Medline]

3 Serve H, Oelmann E, Herweg A, Oberberg D, Serve S, Reufi B, et al. Inhibition of proliferation and clonal growth of human breast cancer cells by interleukin-13. Cancer Res 1996;56: 3583–8.[Abstract]

4 Topp MS, Koenigsmann M, Mire-Sluis A, Oberberg D, Eitelbach F, von Marschall Z, et al. Recombinant human interleukin-4 inhibits growth of some human lung tumor cell lines in vitro and in vivo. Blood 1993;82:2837–44.[Abstract]

5 Freedman VH, Shin S. Cellular tumorigenicity in nude mice: correlation with cell growth in semi-solid medium. Cell 1974;3:355–9.[ISI][Medline]

6 Gross JL, Behrens DL, Mullins DE, Kornblith PL, Dexter DL. Plasminogen activator and inhibitor activity in human glioma cells and modulation by sodium butyrate. Cancer Res 1988;48:291–6.[Abstract]

7 Von Hoff DD. He’s not going to talk about in vitro predictive assays again, is he? [Commentary]. J Natl Cancer Inst 1990;82:96–101.[Abstract]



             
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