Regression of early and intermediate stages of colon cancer by targeting multiple members of the EGFR family with EGFR-related protein.
A role of the epidermal growth factor receptor (EGFR) family has been suggested in colon cancer etiology, progression, and/or severity. Our recently identified pan-erbB inhibitor EGFR-related protein (ERRP) targets EGFRs by attenuating their activation and subsequent signaling leading to cellular growth inhibition. In the present study, we evaluated the therapeutic effectiveness of ERRP on early and intermediate stages of colon cancer by examining regression of chemically induced aberrant crypt foci (ACF) in the colon of CF1 mice and intestinal adenomas in APC(Min+/-) (Min) mice. After formation of ACF or adenomas, the mice were injected (i.p.) with ERRP (50 microg/mouse) for 10 consecutive days. This treatment significantly reduced the number of ACF from 25.0 +/- 3.0 (controls) to 14.9 +/- 1.6 (ERRP-treated; P = 0.011) and also reduced their size (P < 0.01). In Min mice, ERRP caused the regression of adenomas throughout the small intestine (P < 0.05) and reduced their size (P < 0.001). This could partly be attributed to inhibition of proliferation and stimulation of apoptosis in the intestinal mucosa and was associated with decreased activation of several EGFR family members, suppression of downstream effector nuclear factor kappaB and down-regulation of cyclooxygenase-2. ERRP-induced attenuation of EGFR activation could be due to increased sequestration of the ligand(s) by ERRP, rendering them unavailable for binding to and activation of the receptor. In conclusion, our data show that ERRP is effective in regressing both early and intermediate intestinal lesions and could be an effective therapeutic agent for colon cancer.
Schmelz
Eva M
EM
Department of Nutrition and Food Science, Wayne State University, Detriot, Michigan 48220, USA.
Xu
Hu
H
Sengupta
Radha
R
Du
Jianhua
J
Banerjee
Sanjeev
S
Sarkar
Fazlul H
FH
Rishi
Arun K
AK
Majumdar
Adhip P N
AP
D019813:1,2-Dimethylhydrazine; D000236:Adenoma / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002273:Carcinogens; D048708:Cell Growth Processes / Q000187:drug effects; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D029721:Drosophila Proteins / Q000235:genetics / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009367:Neoplasm Staging; D011230:Precancerous Conditions / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011960:Receptors, Estrogen / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology; D016211:Transforming Growth Factor alpha / Q000378:metabolism
D002273:Carcinogens; D029721:Drosophila Proteins; C475538:ERR protein, Drosophila; D016328:NF-kappa B; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors; D019813:1,2-Dimethylhydrazine