Interaction between endothelial cells and the secreted cytokine drives the fate of an IL4- or an IL5-transduced tumour.
Injection of interleukin-4 (IL4) gene-transduced tumour cells into syngeneic immunocompetent mice resulted in tumour rejection in which a key role for eosinophils was suggested. To evaluate whether IL5 inhibits tumour growth by selectively inducing eosinophil recruitment and activation, a poorly differentiated mammary adenocarcinoma cell line (TSA) was transfected with the IL5 gene and the cells secreting IL5 (TSA-IL5) were injected subcutaneously (s.c.) in syngeneic mice. The oncogenicity of TSA-IL5 was compared with that exhibited by TSA cells transfected with the IL4 gene (TSA-IL4) and with the neomycin resistance gene only (TSA-neo). At progressive times after subcutaneous challenge, tumour growth areas were studied histologically, ultrastructurally, and immunohistochemically to identify the reactive cells, visualize tumour vessels, and detect the cytokines and chemokines involved in the anti-tumour reaction. Both the morphological and the functional data showed that TSA-IL5, despite the large eosinophil infiltrate, grew progressively like TSA-neo, suggesting that eosinophils per se do not play a crucial role in TSA tumour rejection. Furthermore, our data indicate that the rejection of TSA-IL4 depends on the IL4-induced expression of VCAM-1 and MCP-1 by endothelial cells. MCP-1 together with VCAM-1 results in recruitment and activation of basophils, mast cells, and macrophages, and hence a pro-inflammatory cytokine cascade that initially favours the influx and activation of neutrophils and finally tumour rejection. In this context, the rejection of TSA-IL4 seems to involve a variety of reactive cells and rests on a continuous cross-talk between basophils, mast cells, macrophages, CD8-positive lymphocytes, and granulocyte subsets, mostly neutrophils.
Di Carlo
E
E
Dipartimento di Oncologia e Neuroscienze, Università G. D'annunzio, Chieti, Italy.
Modesti
A
A
Coletti
A
A
Colombo
M P
MP
Giovarelli
M
M
Forni
G
G
Diodoro
M G
MG
Musiani
P
P
D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D004727:Endothelium / Q000473:pathology; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D015847:Interleukin-4 / Q000235:genetics*; D015848:Interleukin-5 / Q000235:genetics*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000628:therapy* / Q000648:ultrastructure; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation
D015815:Cell Adhesion Molecules; D015848:Interleukin-5; D015847:Interleukin-4