Paracrine factors produced by bone marrow stromal cells induce apoptosis and neuroendocrine differentiation in prostate cancer cells.
BACKGROUND
Preferential bony metastasis of human prostate cancer (PCa) cells contributes to disease mortality and morbidity. Local factors in bone stromal extracellular matrix microenvironment affect tumor growth through paracrine interactions between tumor and stromal cells.


METHODS
Using co-culture and medium transfer, we used several methods to assess interactions between PCa and bone stromal cells using three PCa cell lines: PC3, LNCaP, and the LNCaP derivative, C4-2B.


RESULTS
Co-culture of LNCaP and C4-2B cells with bone marrow stromal cell lines, HS27a and HS5, decreased cell number, as did culture with conditioned medium (CM) harvested from these two cell lines suggesting a soluble paracrine factor was responsible. PC3 cell growth was unaffected. CM harvested from bone stromal cell lines triggered apoptosis in LNCaP and C4-2B cell lines, but not in PC3 cells. Surviving C4-2B cells grown in bone stromal cell CM over several days were growth arrested, suggesting presence of a growth inhibitor. Apoptosis induced by CM was dose-dependent. Flow cytometry demonstrated that over a 5-day culture period in stromal cell CM, LNCaP, and C4-2B cell lines, but not PC3 cells, underwent greater apoptosis than parallel cultures in SF medium. The LNCaP and C4-2B cells showed morphology and biomarker expression consistent with transdifferentiation towards a neuroendocrine phenotype after exposure to stromal cell CM.


CONCLUSIONS
The reactive bone stromal microenvironment initially is hostile to PCa cells producing widespread apoptosis. Activation of transdifferentiation in a subset of apoptotic resistant cells may support phenotypic adaptation during disease progression in bone, eventually favoring lethal disease.
Zhang
Chu
C
Department of Biological Sciences and Center for Translational Cancer Research, University of Delaware, Newark, Delaware, USA.
Soori
Mehrnoosh
M
Miles
Fayth L
FL
Sikes
Robert A
RA
Carson
Daniel D
DD
Chung
Leland W K
LW
Farach-Carson
Mary C
MC
D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary; D002454:Cell Differentiation / Q000502:physiology*; D048708:Cell Growth Processes / Q000502:physiology; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology; D018358:Neuroendocrine Tumors / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
D017077:Culture Media, Conditioned