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Research Tells Us: Never Assume

The reading I’ve done over the past several weeks has reminded me yet again why it is critical that we go back and question our assumptions about cancer.

Assumptions are rooted in the scientific process. Science is all about observing certain phenomena and then creating a hypothesis that can explain what we see. In some cases, we do clinical trials to test the hypothesis. And if the result is what we had thought (hoped) it would be, we accept the hypothesis as the Truth. And then we recommend treatments based on that Truth.

Probably the best example of this in breast cancer was the Truth that breast cancer started in the breast and then, once it was big enough, moved to the lymph nodes under the arm. From there, it spread to the rest of the body. This Truth led surgeons to decide they should treat all breast cancer with a radical mastectomy. They saw this as the best chance for slamming the barn door before the cells got out. Thanks to the many women with early-stage breast cancer who allowed themselves to be randomized in a clinical trial that tested this hypothesis, we now know that more is NOT better as far as surgery is concerned. Women who have a lumpectomy followed by radiation have the same survival rates as women who have a mastectomy.

A new study in Nature suggests there are likely to be many other  dearly held “truths” we will need to question as scientists use new and improved technologies to study cancer cells. This recent study, which looked at liver cancer cells in rats, found that the same type of cell can give rise to different subtypes of cancer. The key factor: the type of cells that were dying in the microenvironment (the neighborhood) around the cancer cell.

How did the researchers even think to study this? They had done a prior experiment in rats that had used two different approaches to deliver the liver cancer-promoting genes. One approach involved injecting cells into the tail vein and letting the blood stream carry them to the liver. The other approach used electroporation, which uses an electric field to introduce chemicals, drugs or DNA into the liver cells. Both techniques got liver cancer to develop in rats, but they caused different types of collateral damage in the surrounding cells—and different types of cancers. The tail vein injection approach caused apoptosis (cell death), and it resulted in hepatocellular carcinoma (HCC), the most common type of liver cancer (about 75 percent of liver cancers are HCC). This type of liver cancer is caused by cirrhosis due to alcohol, hepatitis B or hepatitis C. When electroporation was used, it caused more inflammation in the microenvironment and the cancers that arose were intrahepatic cholangiocarcinomas (ICC), which start in the peripheral bile ducts inside the liver. A follow up study showed that keeping the inflammation from occurring during electroporation caused HCC, not ICC.

This is, of course, a study in rats. And as we know all too well, what happens in rats isn’t necessarily what happens in people. But it is intriguing. And it could have implications for breast cancer, which is known for its different subtypes. Lobular carcinoma got its name because it is found in the lobule; ductal cancer on the other hand is found in the milk duct. We’ve long assumed that one type started from a lobular cell and the other type started from ductal cell. But maybe they just started as a breast cell and the surrounding cells told them to be ductal or lobular. Or could it be that it’s the tissue around the tumor that causes the cancer to be HER2-negative or positive or ER-negative or positive? We’ve assumed it’s caused by something happening inside the cells. But maybe there was something in the microenvironment that surrounded the cancer cells early on that led them to develop into a certain subtype.

As the authors point out, “early events in tumor formation are long over by the time a biopsy sample is taken from a human liver.” Could that be why certain risk factors seem to be associated with different subtypes of breast cancer? Does tamoxifen reduce breast cancer risk by changing the neighborhood? Does exercise? Could we create a breast microenvironment that was inhospitable to cancer cells? This is the type of study that generates more questions than it can possibly begin to answer. And it is definitely research worth watching!