Identification of luminal breast cancers that establish a tumor-supportive macroenvironment defined by proangiogenic platelets and bone marrow-derived cells.
Breast cancer recurrence rates vary following treatment, suggesting that tumor cells disseminate early from primary sites but remain indolent indefinitely before progressing to symptomatic disease. The reasons why some indolent disseminated tumors erupt into overt disease are unknown. We discovered a novel process by which certain luminal breast cancer (LBC) cells and patient tumor specimens (LBC "instigators") establish a systemic macroenvironment that supports outgrowth of otherwise-indolent disseminated tumors ("responders"). Instigating LBCs secrete cytokines that are absorbed by platelets, which are recruited to responding tumor sites where they aid vessel formation. Instigator-activated bone marrow cells enrich responding tumor cell expression of CD24, an adhesion molecule for platelets, and provide a source of VEGF receptor 2(+) tumor vessel cells. This cascade results in growth of responder adenocarcinomas and is abolished when platelet activation is inhibited by aspirin. These findings highlight the macroenvironment as an important component of disease progression that can be exploited therapeutically.


CONCLUSIONS
Currently, processes that mediate progression of otherwise indolent tumors are not well understood, making it difficult to accurately predict which cancer patients are likely to relapse. Our findings highlight the macroenvironment as an important component of disease progression that can be exploited to more accurately identify patients who would benefit from adjuvant therapy.
Hematology Division, Brigham & Women's Hospital, Cambridge, Massachusetts 02115, USA.
Hanna S
HS
Kuznetsov
Timothy
T
Marsh
Beth A
BA
Markens
Zafira
Z
Castaño
April
A
Greene-Colozzi
Samantha A
SA
Hay
Victoria E
VE
Brown
Andrea L
AL
Richardson
Sabina
S
Signoretti
Elisabeth M
EM
Battinelli
Sandra S
SS
McAllister
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology*; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000097:blood / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D051927:CD24 Antigen / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology; D018450:Disease Progression; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000097:blood / Q000473:pathology; D011379:Prognosis; D014183:Transplantation, Heterologous; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D051927:CD24 Antigen; C497889:CD24 protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2