Tamping Down Cancer Metastasis One Gene at a Time 

Stopping cancer metastasis may be as simple as meddling in the complicated relationship between two genes.

Tomoo Iwakuma, MD, PhD, KU Cancer Center Cancer Biology Program member, is seeking to figure out how metastasis (the spread of cancer from the original tumor site) works at its most basic level so that target therapies can eventually be developed to improve a patient’s prognosis.

Though it seems like cancer cells easily invade and spread throughout the body, it actually takes a lot of work. The cells must first break off from the primary tumor and enter the bloodstream. They must survive whatever they encounter in the vessels, from white blood cells to antibodies. Then, the cancer must go through the blood vessel again, establish an environment it can thrive in, and attach itself to another organ.

“There are so many hurdles leading up to metastasis,” said Dr. Iwakuma. “The blood vessel especially is such a tough environment. It’s like a washing machine – everything is being thrown around and there’s no real place to attach. It’s very hard to survive the process so it’s a big deal when the cancer makes it past that point.”

And yet many cancer patients end up with metastasis, leading to death in 90 percent of cases. This is why catching cancer early remains so crucial – if the first sign of cancer can be eradicated, chances for survival increase dramatically. 

Suppressing cancer before it spreads

Dr. Iwakuma has previously studied both p53, a tumor suppressor gene, and the MDM2 oncogene. P53 mutations lead to tumor development, and the overexpression of MDM2 is often associated with both metastasis and poor patient outcomes. MDM2 also causes p53 to break down and lose its tumor suppressing function. Thus, these two genes play an important role in understanding how cancer progression works.

Previously, Dr. Iwakuma and his team looked at another piece of the metastasis puzzle – a protein called MTBP that binds to MDM2.

The relationship between MTBP and MDM2 is the focus of Dr. Iwakuma’s current R01 grant. He is looking at whether the MDM2-MTBP axis has any influence on cancer metastasis.

For this research, his team is using hepatocellular carcinoma (liver cancer) cells. In early results, Dr. Iwakuma has seen that liver cancer with reduced amounts of MTBP had more lymph node metastasis, while increased amounts of MTBP stopped the liver cancer cells from migrating away from the primary tumor site.

Left: The MTBP protein levels are reduced in hepatocellular carcinoma (the most common type of liver cancer) tissues, resulting in more metastasis.

A lack of MTBP is found in about 70 percent of hepatocellular carcinoma cases, and an overexpression of MDM2 is found in about 30 percent of cases, making the link between the two genes an important relationship to dissect.

Based on all of these preliminary results, Dr. Iwakuma is hypothesizing that MTBP does stop metastasis and MDM2 promotes metastasis when it binds to MTBP and stops it from acting as a metastasis suppressor.



Balancing act of MTBP and MDM2

To lay the groundwork for this current work, Dr. Iwakuma seeks to learn more about what MTBP does. He injected osteosarcoma cells (bone cancer) into mice. Some mice were injected with regular cancer cells and some had an increase in MTBP. After about six weeks, the bone cancer had metastasized to the lungs.

In the mice with an overexpression of MTBP, however, there was less metastasis growth and the primary tumor was not affected.  And a later experiment showed that decreasing the amount of MTBP made mouse osteosarcoma cells more invasive, and thus more likely to spread.

From this previous research, Dr. Iwakuma was able to hypothesize that MTBP suppresses cancer metastasis despite the fact that it interacts with MDM2, a tumor promoter.

“Right now we have mice where the MDM2 expression has been altered,” said Dr. Iwakuma. “We are looking to crossbreed those mice with mice that only have 25 percent of the normal amount of the MTBP protein. Then, we can see which one has more metastasis or less metastasis and decipher more of the relationship between MDM2 and MTBP.”

Dr. Iwakuma hopes this work will help to fill in the blanks about how MTBP stops cancer metastasis, and also how MDM2 inhibits the function of MTBP to promote metastasis.

“Once we know how the relationship between the two genes works, we need to determine a way to increase MTBP activity or reduce MDM2 activity as a way to stop metastasis,” said Dr. Iwakuma. “That’s the future direction of this research.”

Funding sources

  • 1R01CA174735: “The Role of MDM2-MTBP Axis in Cancer Metastasis”
  • University of Kansas Cancer Center: Start Up Grant

Relevant publications

  • Iwakuma, Tomoo, and Guillermina Lozano. "MDM2, an introduction." Molecular Cancer Research 1.14 (2003): 993-1000.
  • Terzian, Tamara, et al. "The inherent instability of mutant p53 is alleviated by Mdm2 or p16INK4a loss." Genes & development 22.10 (2008): 1337-1344.
  • Busso, Carlos S., Tomoo Iwakuma, and Tadahide Izumi. "Ubiquitination of mammalian AP endonuclease (APE1) regulated by the p53–MDM2 signaling pathway." Oncogene 28.13 (2009): 1616-1625.
  • Barboza, Juan A., Tomoo Iwakuma, Tamara Terzian, Adel K. El-Naggar, and Guillermina Lozano. "Mdm2 and Mdm4 loss regulates distinct p53 activities."Molecular Cancer Research 6, no. 6 (2008): 947-954.

How Does Cancer Metastasize?

Step 1:
Cancer cells invade the nearby tissue. 
Step 2: Cancer cells infiltrate nearby blood vessels or lymph vessels.
Step 3:
Now in the blood or lymph system, the cancer cells move to other parts of the body.
Step 4:
Once the cancer cells reach a new part of the body, they stop moving, invade the surrounding capillaries and move into nearby tissue.
Step 5: The cancer cells begin to divide at the new location.
Step 6: The newly grown tumors start the growth of new blood vessels to get their own supply of oxygen and nutrients to continue growth.