IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion.
Innate immune cells can constitute a substantial proportion of the cells within the tumor microenvironment and have been associated with tumor malignancy in patients and animal models of cancer; however, the mechanisms by which they modulate cancer progression are incompletely understood. Here, we show that high levels of cathepsin protease activity are induced in the majority of macrophages in the microenvironment of pancreatic islet cancers, mammary tumors, and lung metastases during malignant progression. We further show that tumor-associated macrophage (TAM)-supplied cathepsins B and S are critical for promoting pancreatic tumor growth, angiogenesis, and invasion in vivo, and markedly enhance the invasiveness of cancer cells in culture. Finally, we demonstrate that interleukin-4 (IL-4) is responsible for inducing cathepsin activity in macrophages in vitro and in vivo. Together, these data establish IL-4 as an important regulator, and cathepsin proteases as critical mediators, of the cancer-promoting functions of TAMs.
Gocheva
Vasilena
V
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Wang
Hao-Wei
HW
Gadea
Bedrick B
BB
Shree
Tanaya
T
Hunter
Karen E
KE
Garfall
Alfred L
AL
Berman
Tara
T
Joyce
Johanna A
JA
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D002403:Cathepsins / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D015847:Interleukin-4 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000473:pathology; D008264:Macrophages / Q000201:enzymology* / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000473:pathology
D014408:Biomarkers, Tumor; D015847:Interleukin-4; D002403:Cathepsins