How Blood Cancer Cells Enter and Damage Lungs
A new research led by New York University (NYU) Langone Health has revealed how Leukemia or blood cancer cells enter the lungs, damage tissue, and cause severe breathing problems
A new research led by New York University (NYU) Langone Health has revealed how Leukemia or blood cancer cells enter the lungs, damage tissue, and cause severe breathing problems.
The new study published online June 29 in Nature Immunology addresses acute myeloid leukemia, or AML, a cancer in which cells in the bone marrow - that actually should become blood cells, instead start to multiply abnormally.
Respiratory failure is a common early AML complication caused by cancer cells infiltrating the lungs, but this process has been poorly understood. The researchers say reducing early breathing crises is crucial to giving AML therapies time to be effective.
Study Results
The researchers, by examining lung tissue slices from mice, as well as tissue biopsies of patients with AML lung "involvement", found that AML cancer cells infiltrate the lungs through the thin alveolar wall blood vessels, leaking into connective tissue (stroma).
"Once there, the AML cells change the structure of the stroma by increasing the number of fibroblasts, cells that produce the collagen that provides the strength and elasticity required for breathing. As part of AML, the overactivity of such cells creates scarlike tissue (fibrosis) that hinders breathing", the study authors found.
The study tests also revealed that AML-driven structural changes affect the mix of immune cells in the lungs, with a shift away from cell populations that attack cancer cells e.g., lymphocytes, and toward myeloid cells that dial down immune attack.
Moreover, the study showed that the presence of AML cells came with a significant drop in the number of endothelial capillary aerocytes, cells that enable the lungs to supply oxygen to the bloodstream as part of breathing.
Study Significance
Highlighting the significance of the study, Iannis Aifantis, PhD, Chair of the Department of Pathology at NYU Grossman School of Medicine and a member of NYU Langone's Perlmutter Cancer Center, said, "There has been a lack of understanding in our field as to how leukemia cells invade the lungs, why they trigger respiratory crises, and why steroids counter this to some degree. Our results describe for the first time specific molecular targets that reduce lung infiltration, which new, better-tailored drug classes can be designed against."
Steroid treatment is frequently used when a patient has a breathing crisis, based on doctors' educated guesses or experience rather than on scientific test results. In their analysis, the researchers found that all patients treated with prednisone when their breathing worsened due to leukemic lung infiltration showed dramatically improved respiratory function within 12 hours.
Because AML cells arise in bone marrow, previous studies have examined their relationship to immune cells in the marrow, but not in the lungs.
"In the current study, the researchers combined single -cell, spatial, and functional experiments to unravel interactions between AML and its microenvironment in the lung", the researchers said.
Through mapping the interactions between cell types in leukemic lungs, the team identified two proteins as drivers of widespread lung inflammation that interferes with breathing.
- One was galectin-9, which binds sugar molecules on cell surfaces and helps them communicate.
- The other was the interleukin-33 (IL-33) receptor protein on the surface of leukemia cells, which passes on signals in damaged lung tissue when it docks into its receptor.
The researchers found that more galectin-9 is produced in AML cells because of the inflammation and the cell-cell interactions in the infiltrated lungs. Higher-than-normal levels of IL-33 receptor signaling were also present in the lungs of AML patients.
The study authors showed that blocking the action of either of these signaling pathways stops infiltration of AML cells into the lungs by affecting both immune cells and cancer cells.
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