AnalyzeDirect 
Many scientists are on a quest to stop colon cancer in its tracks. They are specifically gunning for the usual suspects: Pathways that signal cancer cell survival and that disable cancer-inhibiting programmed cell death, apoptosis.
Insulin-like growth factors (IGFs) and their receptors, including IGF1R, lead the pack in triggering these two deadly cancer mechanisms. These specific growth factors and their receptors are not necessarily bad characters. In fact, IGFs play a major role in childhood growth and continued natural growth in adults. Unfortunately, the growth-signaling pathway from IGFs can go awry and activate these two leading cancer mechanisms.
Considerable research has been poured into developing inhibitors to counteract cancer by targeting one of the IGF receptors, IGF1R. A particularly potent one of these chemical agents is PQIP, a small IGF1R inhibitor that targets IGF1R-dependent colon cancer. Scientists in Nebraska, New York and New Mexico collaborated and discovered the extent of the colon cancer-fighting potential of PQIP. This work by Chowdhury et al., published in Clinical and Experimental Pharmacology, involved novel research approaches and yielded some enlightening results.
Previous research using anti-cancer drugs in a mouse model have relied on subcutaneous implantation to grow tumors. However, Chowdhury and colleagues chose a different route for their study of PQIP—orthotopic implantation. They directly implanted GEO cell-line human colon cancer cells in the large intestines of the mice. The idea was to grow the tumors in a location where they would naturally thrive, and for colon cancer, that is the large intestine. GEO is a well-known colon cancer cell line that is well-differentiated and secretes growth factors, so to test the impact of PQIP, lab experiments were performed that involved two sets of male BALB/c nude mice. In the first set of mice, GEO cell-line human colon carcinoma cells were injected in their right flanks where tumors began to grow. Then tumor sections from these mice were harvested and transplanted directly onto the large intestines of the second set of mice.
After a seven-day recovery, the second set of mice were placed into two groups: An active treatment group and a control group. The treated group of mice received daily doses of 75 mg/Kg of PQIP for 21 days. They were also monitored for tumor size via magnetic resonance imaging.
Various investigation modalities were applied at 21 days. Green fluorescent protein (GFP) imaging confirmed the viability and measurement of primary tumors. Histology with transferase-mediated nick end labeling (TUNEL) assays measured programmed cell death rates. Western blot was applied to analyze the harvested GEO colon cancer cells.
Mice in the treatment arm experienced a 5-fold decline in tumor volume compared to the non-treated mice, according to MRI analysis conducted with Analyze.
TUNEL analysis showed an 8-fold higher rate of apoptosis in the treated group.
Western blot analysis of treated tissue samples revealed reduced IGF1R activation and Akt signaling required for tumors to flourish. (Akt signaling can trigger pathways that promote cell survival, proliferation and growth.)
GFP imaging uncovered an interesting finding in the non-treatment arm of the study: the mice exhibited a 3-fold higher fluorescence intensity of GFP-labeled tumors. In other words, the tumors were more pronounced in the untreated mice.
PQIP did not cause substantial toxicity or weight loss in the mice during the treatment phase.
To summarize, with this PQIP study, Chowdhury and colleagues took a unique approach. They used GEO human cancer cell lines rather than IGF1R-dependent engineered cells to test PQIP effectiveness. Orthotopic implantation in the mice also enabled investigators to study human colon cancer in its organ-specific site, the large intestines. Ultimately, the investigators’ work demonstrated the therapeutic potential of using a powerful IGF1R antagonist such as PQIP to inhibit colon cancer cell survival and trigger apoptosis.
Tags: Colon Cancer