Faulty genes are major triggers and drivers of cancer, and the more knowledge we have about them individually, the better we can predict, track, and treat the disease in a way that is specific to individual patients' particular genetic promoters. To do this, researchers need models that are as realistic as possible. Cell and animal models help, but they do not meet the need at the tissue level. Now, using tissue engineering techniques, researchers have created a human colon model that allows them to identify and track the genes that drive colorectal cancer from initial abnormal mass to invasive tumor.
The new "organoid" model is the creation of researchers from Cornell University in Ithaca, NY, Weill Cornell Medicine in New York, NY, and other colleagues, who report their work in the journal Nature Biotechnology.
Co-senior author Michael Shuler, the Samuel B. Eckert Professor of Engineering at Cornell, says:
"You can't really do experiments very well on human tissue, so having a human system, which allows you to look at the genetics in the context of a controlled environment, is a fairly powerful technique."
Years ago, scientists developed a method called "forward genetics" to identify which genetic changes led to disease. The method, often used in fruit flies, involves creating random mutations and then seeing which mutated gene clusters give rise to the disease characteristics.
The new colon model allows researchers to screen for altered genes that trigger and drive colorectal cancer using a forward genetics approach.
To make the model, the team first deleted cells from normal human colon tissue - but without removing the molecules that hold the cells in place and give the tissue its shape (the extracellular matrix). They then repopulated this remaining framework with cells harvested from samples taken during cancer patient colonoscopies, and also from commercial sources.
The idea is that the "recellularized colon model" creates a millimeter-scale tissue microenvironment that favors the expression of the cancer-causing genes.
From in situ to invasion in weeks
Then, using a technique called the "Sleeping Beauty Transposon System," the team tracked the genetic changes that took place in the colon model that were consistent with early stage colorectal cancer.
After running a number of tests, the researchers confirmed that the model does replicate key features of colorectal cancer progression. It recapitulates them from in situ, localized tumor, to invasion in a matter of weeks.
They identified 38 driver genes, including six that had not been linked to colorectal cancer progression before.
The model features all the key characteristics of tissue, such as complex structure, interactions between cells and the extracellular matrix, and having many different types of cell working together.
Prof. Shuler admits they cannot claim the model replicates exactly what happens in a real human body as colorectal cancer progresses. However, it is a complex, human-based system that offers a way to study key steps in the advanced stages of the cancer, which has not been done before.
Co-senior author Nancy Jenkins, professor of oncology at Houston Methodist Research Institute in Texas, says the model will help fulfill an unmet need in cancer research.
The team can already see two directions for the new model. One would be to study the relationship with the immune system, and the other would be to study metastasis - where cells migrate from the colon to other organs, such as the liver.
"Our hope is that a better understanding of the genetics of tumor metastasis will lead to better molecular targeted therapies and/or biomarkers for the treatment of colon cancer."
Prof. Nancy Jenkins
Colorectal cancer - also known as colon cancer - is the third most common cancer in the world, with nearly 1.4 million new cases diagnosed in 2012.