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Tumor Immunology Unit, Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
We read with interest the recent article by Nazareth et al. (1) reporting on the characterization of human lung tumor-associated fibroblasts and their ability to modulate the activation of tumor-associated T cells. We appreciate the newly emerging evidence reporting the impact of the microenvironment on tumor cells in cancer and read with interest the new findings of the above mentioned article on the role of fibroblasts adjacent to tumor cells.
However, we would like to point out that the reported B7-H1 expression by Nazareth et al. (1) in tumor-associated fibroblasts is an in vitro artifact rather than a natural expression phenomenon. We have shown very recently (2) that both normal and tumor-associated fibroblasts obtained from the tissues of breast cancer patients express very low levels (or none) of B7-H1 molecule upon isolation and gradually start to express this molecule upon in vitro culturing of these cells (up-regulation from <5 to 100%). More importantly, fibroblasts obtained from normal people undergoing plastic surgery also demonstrated B7-H1 up-regulation after in vitro culture (up-regulation from 2 to 90%). This phenomenon was found in both fibroblasts and epithelial cells obtained from normal breast as well as foreskin tissues. The B7-H1 up-regulation started from day 1 of culture and peaked on day 10. We have associated the in vitro induction of B7-H1 with cell proliferation because its expression was strongly and significantly associated with the proliferation marker Ki-67. Furthermore, the B7-H1 expression in the fibroblasts was completely diminished after arresting the cells in the G0 phase (the B7-H1 molecule was up-regulated after in vitro reconditioning of these cells).
The molecular basis for the link between proliferation and B7-H1 expression can be explained by the recent findings of Parsa et al. (3) linking the Akt protein (a kinase important for cellular proliferation) to B7-H1 up-regulation. In addition, our previous in vivo study did not find any significant B7-H1 expression in both normal and tumor-associated fibroblasts analyzed on frozen sections isolated from breast cancer tissues as well as normal breast tissues from plastic surgery patients (4). Similar findings were also reported by Mazanet et al. (5), who demonstrated that B7-H1 was barely detectable in normal untreated skin with only a few keratinocytes and occasional vessels showing very weak staining. Although our study was conducted on breast and skin tissues that are different from the non-small cell lung cancer cells reported in work by Nazareth et al. (1), we believe that up-regulation of B7-H1 upon in vitro culture is a common feature for all types of proliferating cells (2).
Nazareth et al. (1) did not study the expression of B7-H1 in histological sections to show an association of this molecule with the tumor-associated fibroblasts. Study of the expression of B7-H1 molecule in vitro does not reflect the actual situation in the cancer patient. Therefore, we believe that such cultured cells obtained from normal tissue with similar or close passage numbers are the right controls for cultured cells obtained from cancer tissues.
References
This article has been cited by other articles:
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  M. R. Nazareth, L. Broderick, M. R. Simpson-Abelson, R. J. Kelleher Jr, S. J. Yokota, and R. B. Bankert Response to Comment on "Characterization of Human Lung Tumor-Associated Fibroblasts and Their Ability to Modulate the Activation of Tumor-Associated T Cells" J. Immunol., July 15, 2007; 179(2): 733 - 733. [Full Text] [PDF]
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