Epithelial to mesenchymal transition in human breast cancer can provide a nonmalignant stroma.
A breast carcinoma biopsy showed cytochemical evidence of epithelial mesenchymal transition and an alpha-smooth muscle actin-positive stromal reaction. To study the lineage, and the nature of the cells in the stromal reaction, we derived a novel cell line, HBFL-1, from the explanted biopsy. HBFL-1 cells are immortal and exhibit a shared non-random X-chromosome inactivation pattern with the epithelial tumor of origin. Yet they closely resemble normal, finite-life-span fibroblasts by morphology, lack of tumor formation in nude mice, marker expression profile, protein pattern using two-dimensional gel electrophoresis and the ability to undergo myofibroblast conversion. HBFL-1 interacts reciprocally with tumor cells in collagen gel to induce activation of MMP2, leading to tumor-like behavior of epithelial colonies. In vivo, HBFL-1 cells resembled normal-derived myofibroblasts and conferred a significant 3.5- to 7-fold increase in MCF-7 tumor size in nude mice. However, that they were indeed not normal fibroblasts was revealed by residual keratin expression and formation of epithelial microfoci in a reconstituted basement membrane and in nude mice. We conclude that breast cancer can generate its own nonmalignant stroma and that one function for this is that of a reciprocal interaction with epithelial tumor cells to facilitate tumor growth.
Petersen
Ole William
OW
Structural Cell Biology Unit, Department of Medical Anatomy, Section A, the Panum Institute, Copenhagen, Denmark. o.w.petersen@mai.ku.dk
Nielsen
Helga Lind
HL
Gudjonsson
Thorarinn
T
Villadsen
René
R
Rank
Fritz
F
Niebuhr
Erik
E
Bissell
Mina J
MJ
Rønnov-Jessen
Lone
L
D001485:Basement Membrane / Q000473:pathology; D014408:Biomarkers, Tumor / Q000032:analysis; D001706:Biopsy; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D018929:Cell Culture Techniques / Q000379:methods; D002471:Cell Transformation, Neoplastic; D041321:Chromosomes, Human, X; D016207:Cytokines / Q000494:pharmacology; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D006801:Humans; D007621:Karyotyping; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008648:Mesoderm / Q000473:pathology; D011944:Receptors, Androgen / Q000032:analysis; D017154:Stromal Cells / Q000166:cytology*; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D016207:Cytokines; D011944:Receptors, Androgen; D020778:Matrix Metalloproteinase 2