Mediators of vascular remodelling co-opted for sequential steps in lung metastasis.
Metastasis entails numerous biological functions that collectively enable cancerous cells from a primary site to disseminate and overtake distant organs. Using genetic and pharmacological approaches, we show that the epidermal growth factor receptor ligand epiregulin, the cyclooxygenase COX2, and the matrix metalloproteinases 1 and 2, when expressed in human breast cancer cells, collectively facilitate the assembly of new tumour blood vessels, the release of tumour cells into the circulation, and the breaching of lung capillaries by circulating tumour cells to seed pulmonary metastasis. These findings reveal how aggressive primary tumorigenic functions can be mechanistically coupled to greater lung metastatic potential, and how such biological activities may be therapeutically targeted with specific drug combinations.
Gupta
Gaorav P
GP
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Nguyen
Don X
DX
Chiang
Anne C
AC
Bos
Paula D
PD
Kim
Juliet Y
JY
Nadal
Cristina
C
Gomis
Roger R
RR
Manova-Todorova
Katia
K
Massagué
Joan
J
D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology*; D002196:Capillaries / Q000254:growth & development; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D066260:Epiregulin; D005260:Female; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000556:secondary*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic
C587880:EREG protein, human; D066260:Epiregulin; C587881:Ereg protein, mouse; D004815:Epidermal Growth Factor; D051546:Cyclooxygenase 2; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1