To understand how to kill a tumor, you have to study the tumor. Historically, much of how scientists understand tumors comes from removing a tumor from a patient's body, putting it in a plastic dish (called a petri dish), and studying whatever cells are grown in this dish. You may be familiar with the book "The Immortal Life of Henrietta Lacks" by Rebecca Skloot. This book talks about HeLa cells, which are cells that were taken from Henrietta's cervical cancer, grown in a dish, and propagated for the past 60+ years as what is called a "cell line". These cells grow and divide indefinitely, and have been propagated and transferred from lab to lab to be studied. HeLa cells are one of the most famous and most-researched cells that have helped scientists better understand cancer. HeLa cells are not the only cell line that exists or has been used to study cancer. There are cell lines from lung cancer tumors, prostate cancer, brain cancer, and most other major cancers. However, there are a few problem with using cell lines to understand and treat cancer.
- Cell lines are EXTREMELY hard to create. As you may imagine, a plastic dish is nothing like the environment inside the body that the tumor was removed from. In the petri dish the cells are put into "media," the liquid that is used to feed the cells in the petri dish, and this media is also nothing like the nutrients and other growth factors feeding the tumor inside the body. Because of this unnatural environment, some of the tumor cells die - and in many cases most or all of the tumor cells die.
- The cells that are left in the petri dish do not accurately represent the tumor anymore. A tumor isn't a whole bunch of identical cells, but rather a tumor contains a lot of genetically different cells. Scientists call this tumor heterogeneity. This is one of the reasons why drug resistant cells emerge after treating a tumor with drugs (like in the case of melanoma described in a previous post). There are already drug resistant cells inside the tumor that don't die when treated with drug. Unfortunately, not all of these different cells in the tumor will live in a petri dish, so only a selected type or types of cells will live and can be studied.
- Even though cell lines had been the most useful tool in the past to understand cancer biology, they are not at all useful in understanding the EXACT tumor from a particular person. What does this mean? For example, drugs that kill HeLa cells in a petri dish might not work to kill another person's cervical cancer because the genetic cause of that cervical cancer is different. In personalized medicine, the goal is to identify the drugs that will work to kill a particular patient's tumor. Because of this, cell lines just aren't good enough.
Scientists have been working on a number of solutions, and I'll talk about four:
- Biobanking. A biobank collects excess tumor tissue from patients who are having a tumor removed as part of a surgery. This tissue is immediately preserved by freezing and can then be used by researchers to study that particular tumor or many tumors of a particular type (e.g., lung cancer). The disadvantage to this is that the tumor sample isn't an unlimited resource. Once the tissue has been used up - it's gone. The remaining examples all focus on growing the tumor tissue so that it can be propagated and used for many experiments.
- Modified cell line growth. HeLa cells were not grown in any special way, but researchers at Georgetown University have found ways to grow tumor cells in a petri dish that are identical to the tumor and nearly all tumors can grow under these conditions. So what are these conditions? The researchers grow cells on top of a layer of mouse cells called feeder cells because they provide the cell-based nutrients to "feed" the tumor and allow it to grow. They also use a particular inhibitor that allows the cells to grow indefinitely. They have created these modified cell lines from different types of tumors, from frozen biobanked tumors, and from as few as 4 live cells. Even though this system, is better, it still doesn't replicate the 3D architecture of a tumor...
Organoids. As you would expect the word to mean, an organoid is a mini 3D organ bud grown in a dish. Don't imagine a teeny tiny beating heart. These organoids are just clumps of cells, but an organized clump of cells that can help better understand cells and organs. The discovery of how to create organoids was so interesting that it was a 2013 Big Advance of the Year by The Scientists magazine. Scientist have also found a way to grow cancer cells into these 3D organoid structures. With tumor organoids, researchers can both study the genetics of the tumor (like you can with cell lines) as well as how the tumor behaved in a 3D environment that is more similar to what the tumor encounters in the body. But what if we could do even better?
- Patient-derived xenografts are when tumor tissue is taken directly from a patient's tumor and put directly into a mouse. Why would this be so awesome? The environment inside a mouse is more similar to the environment that the tumor is used to inside a person's body. The cells are less likely to die because they aren't living in unnatural plastic. Also, a whole piece of tumor can be implanted into the mouse, maintaining the tumor cells connections to neighboring cells, which are critical for the tumor cells to communicate with one another for survival.
With all of these systems available to study tumors from a specific patient, what are scientists actually doing with these cells? In some cases, they are being used to sequence the genomes of the tumors to identify mutations that may be causing the tumor. If a tumor can be grown so that there is a lot of it, the tumor cells themselves can also be used to test treatments either in a dish or inside of a mouse. Imagine a cancer patient getting their tumor removed, part of the tumor is grown in one of the ways described above. Then the tumor is exposed to the top 10, or 50 or 100 anti-tumor drugs or combination of drugs to see what kills the tumor.
This drug or combo of drugs can then be used to treat the patient. There are companies that are currently working on doing exactly this (check out Champions Oncology) so this "big dream" may soon become a cancer patient's more promising reality.
Dr. Cathy Seiler is the Program Manager for the tissue biorepository at St. Joseph's Hospital and Barrow Neurological Institute. She has her BA in Biochemistry and Molecular Biology from Boston University and PhD in the Biological Sciences from Cold Spring Harbor Laboratory. Her research and teaching focuses on genetics, cancer, and personalized medicine. Find her on Facebook at www.facebook.com/thingsitellmymom