Humanized gene replacement in mice reveals the contribution of cancer stroma-derived HB-EGF to tumor growth.
Tumor progression is a complex process that involves the interaction of cancer cells with the cancer-surrounding stromal cells. The cancer stroma influences the cancer cell growth and metastatic potential. The EGF family growth factor HB-EGF is synthesized in cancer cells and plays pivotal roles in oncogenic transformation and tumor progression, but the contribution of HB-EGF expressed in tumor stromal cells to tumor growth remains unclear. In the present study, we found that HB-EGF was expressed in host-derived cancer stromal cells in xenograft and allograft mouse tumor models. CRM197 is a specific inhibitor of human HB-EGF that has no effect on mouse HB-EGF. To elucidate whether host-derived stromal HB-EGF contributes to tumor growth, we generated knock-in mice expressing a CRM197-inhibitable humanized mutant form of HB-EGF. Administration of CRM197 to humanized knock-in mice that were bearing tumors derived from human or mouse cancer cells revealed that inhibition of host-derived stromal HB-EGF by CRM197 significantly reduced tumor growth. These results suggest that HB-EGF in the cancer-associated stroma plays a significant role for tumor growth, and that the HB-EGF derived from the stroma, as well as that expressed by cancer cells, is a potential target for cancer therapy. The present results also suggest that the humanized HB-EGF knock-in mice could be utilized for pathophysiological studies of HB-EGF as well as the development of therapeutic strategies targeting HB-EGF.
Ichise
Tomoko
T
Department of Cell Biology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
Adachi
Satoshi
S
Ohishi
Minako
M
Ikawa
Masahito
M
Okabe
Masaru
M
Iwamoto
Ryo
R
Mekada
Eisuke
E
D000818:Animals; D001426:Bacterial Proteins / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D055879:Gene Knock-In Techniques; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D017154:Stromal Cells / Q000378:metabolism; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous
D001426:Bacterial Proteins; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; C028581:CRM197 (non-toxic variant of diphtheria toxin)