Despite dramatic recent advances in treatment, colorectal cancer killed more than 49,000 Americans last year, according to the National Cancer Institute, making it the second most lethal malignancy after cancers of the lung and bronchus.
Determined to reduce the death toll, researchers at Vanderbilt University Medical Center recently put on their 3-D “glasses” and took a look at colorectal cancer from a new perspective. What they saw was rather astonishing.
Three years ago Robert Coffey Jr., M.D., and his colleagues reported that when a human colorectal cancer cell line was grown in a three-dimensional culture, it separated into two radically different colonies of hollow, single-layered, polarized cystic cells (CC) and solid masses of spiky cells (SC).
While CC is strongly inhibited by cetuximab, a drug that neutralizes the cancer-driving potential of the epidermal growth factor receptor (EGFR), SC keeps spreading, thanks to two growth-activating receptor tyrosine kinase enzymes, MET and RON.
In the current study, the researchers found they could break SC’s resistance to cetuximab by blocking these enzymes using an FDA-approved compound, crizotinib.
Their findings, reported March 20 in the Proceedings of the National Academy of Sciences (PNAS), suggest that the 3-D approach is a potentially powerful way to improve early diagnosis and treatment of colorectal cancer and possibly other solid tumors.
The 3-D culture was crucial in making this discovery. When grown in two dimensions, CC and SC colonies look the same and neither responds to cetuximab. But by entering the third dimension, the researchers were able to link CC and SC’s unique characteristics to differences in gene expression.
Coffey directs the Epithelial Biology Center and is an Ingram Professor of Cancer Research. These findings, he noted, “support a major tenet of the Epithelial Biology Center, that is, that studying the behavior of cancer cells in 3-D reveals far more clinically relevant information than more conventional 2-D culture.”
It will take a lot more time in the lab before colorectal cancer will give up all of its secrets. But this much seems to be certain: even the most unyielding conundrum can be solved simply by looking at it in another way.
Coffey’s colleagues included first author Cunxi Li, M.D., Ph.D., second author Bhuminder Singh, Ph.D., Ramona Graves-Deal, and Vanderbilt faculty members Qi Liu, Ph.D., Oliver McDonald, M.D., Ph.D., Mary Kay Washington, M.D., Ph.D., and Ginger Milne, Ph.D.
The study was supported in part by National Institutes of Health grants CA046413 and CA095103.
