Surveillance of spontaneous breast cancer metastasis by TRAIL-expressing CD34⁺ cells in a xenograft model.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), delivered as a membrane-bound molecule expressed on the surface of adenovirus-transduced CD34(+) cells (CD34-TRAIL(+)), was analyzed for its apoptotic activity in vitro on 12 breast cancer cell lines representing estrogen receptor-positive, HER2(+) and triple-negative (TN) subtypes and for its effect on tumor growth, vascularization, necrosis, and lung metastasis incidence in NOD/SCID mice xenografted with the TN breast cancer line MDA-MB-231. Mesenchymal TN cell lines, which are the richest in putative tumor stem cells among the different breast cancer cell subtypes, were the most susceptible to apoptosis induced by CD34-TRAIL(+) cells. Indeed, tumor cell "stemness", assessed based on the proportion of CD44(+)/CD24(-/low) cells, was significantly correlated with susceptibility to TRAIL. Moreover, in vitro cytotoxicity experiments showed that CD34-TRAIL(+) cells selectively targeted CD44(+)/CD24(-/low) cells. Although in vivo treatment with CD34-TRAIL(+) cells did not lead to tumor growth inhibition, treated mice revealed significantly larger areas of necrosis associated with damage of tumor vasculature than did control mice. Moreover, lungs from MDA-MD-231 tumor-bearing mice were completely free of metastases at 12 days after the last injection of CD34-TRAIL(+) cells, whereas metastases were present in all control mouse lungs. An anti-metastatic effect of CD34-TRAIL(+) cells was also observed in a model of experimental lung metastases. The correlation between in vitro susceptibility to membrane-bound TRAIL and tumor stem cell content, together with CD34-TRAIL(+) cell-induced inhibition of the metastatic process, points to the selective targeting of cancer stem cells by CD34-armed cells and the potential value of such cells in eradicating tumor stem cells before the onset of overt metastases.
Dipartimento di Scienze biomediche per la salute, Università di Milano, Via Mangiagalli 31, 20133 Milan, Italy.
Anna
A
Rossini
Marta
M
Giussani
Arianna
A
Giacomini
Carla
C
Guarnotta
Elda
E
Tagliabue
Andrea
A
Balsari
D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D047368:Tumor Burden
D018952:Antigens, CD34; D053221:TNF-Related Apoptosis-Inducing Ligand