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How Do Tumors Spread? Understanding the Tumor Microenvironment

Rosandra N. Kaplan, MD, pediatric oncologist and physician scientist at the National Cancer Institute, explains how understanding the tumor microevironment can fuel potential treatments.

“A lot of cancer patients think their immune system failed them — that it did not recognize the cancer and was not able to get rid of it,” says Rosandra N. Kaplan, MD, a pediatric oncologist, physician scientist, and a senior investigator of the Pediatric Oncology Branch at the National Cancer Institute. The truth is more complex. “The same features that repair us also help our tumors grow and spread,” says Dr. Kaplan.

The Osteosarcoma Institute (OSI) spoke with Dr. Kaplan to understand why the body can cause tumors to grow and how these insights can unlock new treatments for osteosarcoma.

The Ecosystem Surrounding a Tumor

Dr. Kaplan describes cancer as a little city with its own structure and environment, requiring its own blood supply. “A tumor is constantly interacting with its environment,” says Dr. Kaplan. “From the very beginning, tumors interact with bone marrow, blood vessels, the immune system and every aspect of the body as they grow.”

Instead of preventing tumor growth, the tumor microenvironment — including the body’s immune system — often recognizes cancer cells not as foreign, but as injured tissue that needs to heal. Unfortunately, the same healing process that repairs our normal tissue often enables tumors to grow larger, and even spread to other parts of the body.


Rosandra N. Kaplan, MD

Here is how this works in practice: First, bone marrow derived cells (mostly myeloid cells, a type of immune cell) go to the primary tumor to try to fight the cancer. However, since the cancer is made up of the body’s own cells— rather than a foreign entity (like bacteria or viruses in an infection) — the body is not activated to kill but tries to repair the tumor instead. This in turn helps it grow and spread.

Bone marrow derived cells then travel to other sites in the body, such as the lungs, and can help the cancer cells survive and grow there as well. Dr. Kaplan and her team found that the myeloid cells travel to special sites that have blood vessels and stroma, which form a nest similar to a tissue injury repair site. Dr. Kaplan likens this process to a welcome committee. It is as if you moved to a new city, and the one person you know introduces you to all their friends.

Healing or Hurting?

“The more we look, the more complex it is,” says Dr. Kaplan. “A Harvard pathologist once said, ‘Cancer is like a wound that never heals.’ When your cancer grows, your body has to respond to it, but because it is part of you, it is not considered an infection and it responds more like an injury. This leads to the part of the immune system that fights invaders to be quieted, and the part of the immune system that promotes repair to be activated.” The more the body tries to heal the “wound,” the more it can promote the spread of cancer.

“At first, the immune system is really trying to fight the cancer, but it gets completely overwhelmed. The immune system then contributes to the problem by activating the part of the body that is trying to heal.” — Rosandra N. Kaplan, MD

“At first, the immune system is really trying to fight it, but it gets completely overwhelmed. The immune system then contributes to the problem by activating the part of the body that is trying to heal,” says Dr. Kaplan.

Zooming in on the “Mom Cells”

The specifics of Dr. Kaplan’s research will be the subject of a future article, but the basic premise is that the non-tumor cells and matrix in the cancer have a very important role in cancer development, growth, and spread. These cells and matrix communicate and organize to make the cancer cells better able to survive, resist treatment, and persist in a new environment. Too often, the body’s injury repair response makes cancer worse.

One area of Dr. Kaplan’s research focuses on myeloid cells, which she terms the “moms” of the immune system. Much more focus has been on T cells since they have the ability to directly kill tumor cells or cells infected with virus or bacteria. The myeloid cells are a group of very fluid, adaptable cells holding many different jobs in responding to infection or injury. “They suss out danger and are the first to respond to a problem. They are the last to leave the party, and they clean everything up.” Myeloid cells eat up cells that are dead, damaged, or mutated. They also travel through the bloodstream to rally other cells to address the problem area when they detect injury, damage, or infection.

This rapid communication may be the reason that osteosarcoma can metastasize to distant parts of the body, moving from a bone in the leg or a shoulder to the lung or another bone, for example. Dr. Kaplan’s team has found that osteosarcoma is chock full of myeloid cells. Dr. Kaplan is attempting to genetically engineer myeloid cells to help instruct the T cells and NK cells to kill cancer, instead of fueling cancer by telling the T cells and other cells to stand down.

“When I first started studying myeloid cells, endothelial cells, and stromal cells with David C. Lyden, MD, PhD, very few people cared about the microenvironment — they were very focused on the genomics of the cancer,” says Dr. Kaplan. “Genomics of the tumor is critical — it is like the foundation of the house — but you also need to know what the rooms look like.” Through her research, she hopes to illuminate a key element of cancer metastasis to ultimately create more effective osteosarcoma therapies.

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