In-vivo activation of Raf-1 inhibits tumor growth and development in a xenograft model of human medullary thyroid cancer.
Apart from surgical resection, there are no effective therapies for medullary thyroid cancer, a neuroendocrine tumor derived from parafollicular C cells. We have previously shown that activation of raf-1 in TT-raf cells by estradiol suppresses tumor cell growth and calcitonin secretion in vitro. TT-raf cells are a human medullary thyroid cancer cell line that contains an estrogen-inducible raf-1 construct. The in-vivo effects of raf-1 activation in this cell line, however, have not been characterized. Therefore, we utilized TT or TT-raf cells in a murine subcutaneous xenograft model to study tumor development and growth. Activation of raf-1, in mice with TT-raf tumors, led to a significant decrease in medullary thyroid cancer tumor formation. Control groups, however, had a high rate of medullary thyroid cancer tumor development. These data indicate that raf-1 activation by estradiol treatment in this TT-raf xenograft model inhibited tumor development. Furthermore, to determine whether raf-1 activation could also inhibit the growth of established tumors, estradiol and control pellets were implanted after tumor development. The TT-raf group that received estradiol pellets showed an 8-fold decrease in tumor volume compared with the TT-raf control group. Taken together, these results suggest that in-vivo activation of raf-1 in a murine model of medullary thyroid cancer not only led to a reduction in tumor development, but also inhibited the growth of established tumors. These results suggest that strategies to activate the raf-1/MEK/ERK1/2 signaling pathway may be a viable approach to treat patients with metastatic medullary thyroid cancer.
Vaccaro
Abram
A
Endocrine Surgery Research Laboratories, Department of Surgery and University of Wisconsin Comprehensive Cancer Center, University of Wisconsin, Madison, Wisconsin, USA.
Chen
Herbert
H
Kunnimalaiyaan
Muthusamy
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D053379:Chromogranin A / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009490:Neurosecretory Systems / Q000187:drug effects; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D053379:Chromogranin A; D019908:Proto-Oncogene Proteins c-raf