SDF-1alpha regulation in breast cancer cells contacting bone marrow stroma is critical for normal hematopoiesis.
Breast cancer cells (BCCs) show preference for the bone marrow (BM). An animal model showed 2 populations of BCCs in the BM with regard to their cycling states. An in vitro model of early BC entry into BM showed normal hematopoiesis. Here, we show a critical role for BCC-derived SDF-1alpha in hematopoietic regulation. The studies used a coculture of BM stroma and BCCs (cell lines and stage II BCCs). Northern blots and enzyme-linked immunosorbent assay (ELISA) showed gradual decreases in SDF-1alpha production in BCCs as they contact BM stroma, indicating partial microenvironmental effects caused by stroma on the BCCs. SDF-1 knock-down BCCs and increased exogenous SDF-1alpha prevented contact inhibition between BCCs and BM stroma. Contact inhibition was restored with low SDF-1alpha levels. Long-term culture-initiating assays with CD34(+)/CD38(-)/Lin(-) showed normal hematopoiesis provided that SDF-1alpha levels were reduced in BCCs. Gap junctions (connexin-43 [CX-43]) were formed between BCCs and BM stroma, with concomitant interaction between CD34(+)/CD38(-)/Lin(-) and BM stroma but not with the neighboring BCCs. In summary, SDF-1alpha levels are reduced in BCCs that contact BM stroma. The low levels of SDF-1alpha in BCCs regulate interactions between BM stroma and hematopoietic progenitors, consequently facilitating normal hematopoiesis.
Moharita
Anabella L
AL
UMDNJ-New Jersey Medical School, Newark, NJ 07103, USA.
Taborga
Marcelo
M
Corcoran
Kelly E
KE
Bryan
Margarette
M
Patel
Prem S
PS
Rameshwar
Pranela
P
D000368:Aged; D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D001943:Breast Neoplasms / Q000737:chemistry / Q000473:pathology*; D002450:Cell Communication; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018920:Coculture Techniques; D003260:Contact Inhibition; D005260:Female; D017629:Gap Junctions; D006410:Hematopoiesis; D006801:Humans; D051379:Mice; D008875:Middle Aged; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering / Q000494:pharmacology; D017154:Stromal Cells / Q000473:pathology*
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering