Stroma cells: a novel target of herceptin activity.
OBJECTIVE
Stroma cells play a relevant role in tumor development and progression. We investigated the activity of herceptin (HER), a humanized monoclonal antibody widely used for the treatment of HER2-overexpressing epithelial cancer, toward stroma cell lines L87/4 and L88/5.


METHODS
We studied the antiproliferative potential of HER and role of human serum in HER activity. We also investigated the ability of HER to alter ancillary functions of L87/4 and L88/5, such as support to long-term hematopoiesis, growth factor production, breast cancer cell adhesion, and proliferation.


RESULTS
Flow cytometry showed that HER2 membrane expression in L87/4 and L88/5 stroma cells was intermediate between the expression in HER2-negative/dim MCF-7 breast cancer cells and HER2-bright SK-BC3 breast cancer cells. HER2 gene amplification was not detected by fluorescence in situ hybridization in either stromal cell lines. HER significantly inhibited L87/4 and L88/5 proliferation. Mean ID(50)s were found to be 2000 and 1700 micro g/ml for L87/4 and L88/5, respectively, after 3-day exposure and 800 micro g/ml for both cell lines after 9-day exposure. The presence of 10% human serum in the culture increased HER inhibitory activity. IC(50) of stroma cells was found to be intermediate between HER2-bright breast cancer cells (SK-BC3) and HER2-negative/dim breast cancer cells (MCF-7). The drug did not significantly affect the ability of stroma cells to support long-term hematopoiesis in the cobblestone area forming cell assay. In contrast, in coculture assay, MCF7 cells demonstrated a worse adhesion and growth capability on HER-treated stroma layers when compared with untreated stroma. Moreover, HER significantly reduced vascular endothelial growth factor production by L88/5 cells.


CONCLUSIONS
Our data support the novel finding that HER may have a relevant activity against stroma cells.
Division of Hematology-Oncology, Department of Medicine, European Institute of Oncology, 20141 Milan, Italy.
Chiara
C
Corsini
Patrizia
P
Mancuso
Saki
S
Paul
Alessandra
A
Burlini
Giovanni
G
Martinelli
Giancarlo
G
Pruneri
Francesco
F
Bertolini
D000911:Antibodies, Monoclonal / Q000378:metabolism*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002448:Cell Adhesion; D002455:Cell Division; D002478:Cells, Cultured / Q000187:drug effects; D018920:Coculture Techniques; D004815:Epidermal Growth Factor / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006410:Hematopoiesis; D006801:Humans; D016130:Immunophenotyping; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology; D000068878:Trastuzumab; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004815:Epidermal Growth Factor; D016222:Fibroblast Growth Factor 2; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D042461:Vascular Endothelial Growth Factor A