Punita Dhawan, Ph.D.
Researchers track protein that turns good cells bad
Cancer cells are not good neighbors. First they stop saying hello, and then before you know it, they're disregarding property lines and setting up housekeeping in your yard, the yard across the street, and yards all across town.
Vanderbilt-Ingram Cancer Center investigators have discovered a new molecular change that accompanies this transformation of colon cells from good neighbors to bad.
They report in the July Journal of Clinical Investigation that the protein claudin-1 plays a causal role in colon cancer and metastasis.
The findings point to claudin-1 as a potential biomarker and therapeutic target for colon cancer.
Claudin-1 is the major protein member of the “tight junctions” that bind cells together. Investigators speculated that these spots of cellular glue would be lost in cancer cells that break from a primary tumor to spread to distant sites, said lead researcher Punita Dhawan, Ph.D., assistant professor of Surgery in the Division of Surgical Oncology.
Instead, Dhawan and colleagues found that claudin-1 levels increase in a stage-specific manner. The levels are low in normal tissue from patients, rise higher in primary tumor samples, and then rise even higher in metastatic tumor tissue.
Accompanying this increase in claudin-1 levels is a change in the protein's location — it moves from the cell membrane, where it normally functions in the tight junction, to a position inside the cell and even inside the nucleus.
“We found this very surprising and intriguing: we wondered if claudin-1 in the nucleus could be signaling or regulating gene expression,” Dhawan said.
To investigate these possibilities, Dhawan and colleagues turned to a cell model system. They used two cell lines derived from the same patient — one from the patient's primary tumor and one from a metastatic tumor.
As they expected, the metastatic cell line had higher levels of claudin-1.
“We thought this would be an excellent model system, because the genetic background of the two cell lines is exactly the same,” Dhawan said. “Our question was — if we manipulate claudin-1 expression, can we change the cellular characteristics of these cells?”
The answer was yes. When the investigators increased claudin-1 levels in the primary tumor cells, the cells gained “tumorigenic and metastatic capabilities” and readily metastasized in an in vivo model, Dhawan said.
Likewise, when the researchers reduced claudin-1 in the metastatic cells, the cells lost their metastatic characteristics both in vitro and in vivo.
These results prompted the investigators to ask how claudin-1 is changing the cancer-related characteristics of the cell. Their studies suggest that claudin-1 is changing the expression and activity of the proteins E-cadherin and beta-catenin, other junction proteins already implicated in many different kinds of cancer.
“We're very excited by the possibility that claudin-1 might make a useful biomarker for colon cancer progression and that inhibiting its expression might have therapeutic potential,” Dhawan said.
A new multidisciplinary initiative to apply nanotechnology to cancer could also use claudin-1 as a target, said the program's leader Lynn M. Matrisian, Ph.D., Ingram Distinguished Professor and Chair of Cancer Biology. The initiative is developing technology that will deliver nanoparticles, which can also carry imaging agents and/or therapeutic agents, specifically to cancer cells.
Dhawan and her colleagues are continuing to build the case against claudin-1 for its role in colon cancer. They're looking at the association between the expression and localization of claudin-1 and patient survival. They're also searching for the nuclear targets of claudin-1 — the genes that it regulates to exert its pro-cancer, pro-metastasis activity.
The research was supported by the National Institutes of Health, Vanderbilt's SPORE grant in gastrointestinal cancer, and the Vanderbilt-Ingram Cancer Center. Authors of the JCI paper include R. Daniel Beauchamp, M.D., Amar B. Singh, Ph.D., Natasha G. Deane, Ph.D., YiRan No, Sheng-Ru Shiou, Carl Schmidt, M.D., John Neff, and M. Kay Washington, M.D.