The secret of lymph: How lymph nodes help cancer cells spread

Date:
August 19, 2020
Source:
UT Southwestern Medical Center
Summary:
For decades, physicians have known that many kinds of cancer cells
often spread first to lymph nodes before traveling to distant
organs through the bloodstream. New research provides insight into
why this occurs, opening up new targets for treatments that could
inhibit the spread of cancer.



FULL STORY ==========================================================================
For decades, physicians have known that many kinds of cancer cells
often spread first to lymph nodes before traveling to distant organs
through the bloodstream. New research from Children's Medical Center
Research Institute at UT Southwestern (CRI) provides insight into why
this occurs, opening up new targets for treatments that could inhibit
the spread of cancer.


==========================================================================
The study, published today in Nature, found melanoma cells that pass
through the lymph nodes pick up a protective coating, allowing them to
survive high levels of oxidative stress in the blood and go on to form
distant tumors.

Most cancer deaths happen after cancer spreads to other parts of the
body through a process known as metastasis. This occurs when cancer
cells from the primary tumor spread through blood vessels or migrate
through lymphatic vessels before entering the blood.

"Previous research has focused on how cancer cells metastasize through
the blood, but very little was known about how these cells compare
to cells that metastasize through lymphatics," says Sean Morrison,
Ph.D., the director of CRI and a Howard Hughes Medical Institute (HHMI) investigator. "Our data suggest that passing through the lymphatics can
promote the survival and spread of melanoma cells by protecting the cells
from the oxidative stress they normally experience during metastasis."
The researchers observed how human melanoma cells behaved when injected intravenously or into the lymphatic system of mice. They found that
cancer cells injected into lymph nodes had a better chance of surviving
and forming tumors than those injected directly into the blood.

Researchers hypothesized this difference could be explained by the high
levels of oxidative stress cancer cells experience when they migrate
through the blood. Exposure to oxidative stress in the blood is one reason
why metastasis is a very inefficient process in which most cancer cells
die before they have an opportunity to grow at a distant site.

"After further analysis, we discovered that the oxidative stress in the
blood causes the cancer cells to undergo a specific form of cell death
called ferroptosis," says Jessalyn Ubellacker, Ph.D., lead author of the
study and a postdoctoral researcher in the Morrison lab. "In contrast,
cancer cells in lymph experience lower levels of oxidative stress and are protected from ferroptosis." To better understand why melanoma cells
undergo ferroptosis in the blood but not the lymph, researchers looked
for metabolic differences between cancer cells in the blood versus the
lymph. They discovered cancer cells from the lymph had higher levels
of a monounsaturated fatty acid known as oleic acid, which is the main component of olive oil. They also found this monounsaturated fatty acid
was incorporated into the membranes of cancer cells in the lymph.

This diluted polyunsaturated fatty acids in the membranes of these cells, inhibiting the chemical reactions that lead to ferroptosis and protecting
the cells.

This protective coating of oleic acid from the lymph thus allowed the
cancer cells to safely enter the blood, travel to other locations, and
form metastatic tumors. This explains why cancer cells often form tumors
first in lymph nodes before metastasizing to distant sites through the
blood: They are able to load up on antioxidants in the lymph that protect
the cells when they subsequently enter the blood.

"Now that we understand more about why cancer cells are most likely
to metastasize initially through lymph, it raises the possibility of
treating patients with drugs that target those protective mechanisms in
the lymph to inhibit the early stages of metastasis," says Morrison.


========================================================================== Story Source: Materials provided by UT_Southwestern_Medical_Center. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Jessalyn M. Ubellacker, Alpaslan Tasdogan, Vijayashree Ramesh,
Bo Shen,
Evann C. Mitchell, Misty S. Martin-Sandoval, Zhimin Gu, Michael L.

McCormick, Alison B. Durham, Douglas R. Spitz, Zhiyu Zhao, Thomas P.

Mathews, Sean J. Morrison. Lymph protects metastasizing melanoma
cells from ferroptosis. Nature, 2020; DOI: 10.1038/s41586-020-2623-z ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200819110921.htm

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