Cancer Creates Special Agents Out of Immune Cells

“Metastatic” is a word that can send shivers down the spine of almost anyone who hears it. As 1 out of 2 men and 1 out of 3 women will develop cancer in their lifetime, nearly everyone knows someone who has been affected by a cancer diagnosis, and perhaps even someone who has had cancer that was called metastatic. Metastasis means that cancer cells have traveled from the place where they originally developed to a new site in the body, and it is associated with most of the negative effects of cancer, including a higher risk of death. 

Cancer researchers have been working for years to identify the methods cells use to make this migration possible. Renumathy Dhanasekaran and colleagues recently showed that two molecules, Myc and Twist1, work together to cause metastasis in a type of liver cancer called hepatocellular carcinoma. This nefarious duo cooperates to turn the body’s own immune cells against itself. 

Myc and Twist1 in mice

Myc and Twist were already known to be important players in cancer cells, so the scientists weren’t surprised when they expressed, or increased, Myc in mouse livers and those mice developed liver cancer.  Myc and Twist1 are both proteins: workhorse molecules that use their geometric shapes and particular chemical properties to accomplish different tasks within the cell, controlling everything from how often they divide to how they communicate with one another. When the scientists expressed Twist1 in mouse livers, they didn’t see the same effect as they saw with Myc. However, when Twist1 and Myc were expressed together, not only did the mice develop liver tumors, but the percentage of mice that developed metastasis jumped from 2% with Myc alone all the way to 90%. This experiment suggests that Myc and Twist1 work together to help cancer cells metastasize. How do these two proteins accomplish this? They trick the immune system into turning against the body.

Myc and Twist1 affect immune cell communication

Immune cells speak a chemical language. They communicate through small messenger molecules called cytokines. Think of a cytokine as a letter, and when it finds a cell with the correct mailbox, or receptor, it can deliver its directive and affect the behavior of the recipient cell. Different cytokines carry different messages; some, for example, tell cells to grow and divide, while others tell cells to move and travel to a particular location in the body. 

When Myc and Twist1 are expressed in liver cells, they cause those cells to send out many cytokines, including two called Ccl2 and Il-13. These cytokines then communicate with immune cells called macrophages and recruit them to their side, making them Tumor Associated Macrophages, or TAMs. But just how much did they convert the macrophages to their side? Are the TAMs just grunts, or are they playing a bigger role in the cancer’s master plan? Are they just bystanders to the crime, or are they, in fact, directly responsible for the increased metastasis in the Myc and Twist1 combination mice? 

TAMs as converted cancer special agents

The research group wanted to know the exact role TAMs played. To do so, they depleted the number of macrophages in these mice, to see what would happen if the TAMs were not around to help the cancer. They could then better understand what TAMs were doing by looking at the void left behind in their absence. Amazingly, when TAMs were depleted, cancer metastasis was significantly reduced. This shows that the macrophages, converted into TAMS by the cytokines released from Myc and Twist1-expressing cancer cells,  are directly contributing to increased metastasis (Figure 1).

Figure 1: Myc/Twist1-driven metastasis. Panel 1) In the context of liver cancer, some tumor cells (green) contain high levels of the proteins Myc and Twist1. Panel 2) Myc and Twist1 cause cancer cells to secrete cytokines (blue dots), such as Ccl2 and Il-13. These cytokines can travel from the tumor into the bloodstream, where they interact with macrophage precursors (purple). Panel 3) Influenced by the cytokines, the macrophage precursors travel out of the bloodstream to the tumor site, where they become TAMS. Panel 4) TAMS can make cancer cells more invasive, helping them move into the bloodstream and metastasize (spread) to different places in the body.

Having shown how Myc and Twist1 work together in mice to increase cancer metastasis, they looked at previously published data on cancer in humans. They found that across many different types of cancer, patients who had higher levels of Myc and Twist1 co-expression had significantly worse disease free survival. Similarly, specifically looking at hepatocellular carcinoma data, cancers that expressed both Myc and Twist1 had worse outcomes for patients than those that expressed either protein alone. They even saw an increase in TAMs with patients who had higher Myc and Twist1 levels. While mouse experiments are a great place to start in scientific research, mice and humans have many differences in their biology, so this human data is very promising for the potential of applying this research in medicine.

Impact on Cancer Therapy 

How can we apply this data to future cancer therapy? Affecting the expression of Myc or Twist1 could be a very difficult task, as they live inside the cells past many barriers, making them hard for drugs to reach. However, the cytokines they cause cancer cells to secrete are much more accessible, as they travel through the spaces between cells to recruit macrophages. The researchers decided to try to intercept the metastasis messages by inhibiting Ccl2 and Il13 with antibodies. Inhibiting Ccl2 alone led to a 7-fold decrease in metastasis and inhibiting Il13 alone led to a 2.5-fold decrease. However, when both Ccl2 and Il13 were inhibited, the decrease in metastasis was 14 fold.

Cytokine levels are easy to measure in a cancer patient’s blood. Imagine being able to take a sample of someone’s blood who was suffering from cancer, test that sample to see if Ccl2 and Il13 were being expressed in high amounts, and then, if the levels were high, give that patient antibodies that target those cytokines and help decrease the chance that that patient’s cancer could metastasize. This kind of personalized medicine is the future many dream of for cancer therapy, and each day it is moving more from the future and into the present. Cancer cells may have some sneaky plans they employ to hijack our immune cells, but now that we know their schemes, we can work to foil their plots!

 

Cover image: VectorStock, ID 6521106, Artist ssstoker

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