Circulating Lymphangioleiomyomatosis Tumor Cells With Loss of Heterozygosity in the TSC2 Gene Show Increased Aldehyde Dehydrogenase Activity

Gustavo Pacheco-Rodríguez; Wendy K Steagall; Leigh Samsel; Pradeep K Dagur; J Philip McCoy; Ilker Tunc; Mehdi Pirooznia; Ji-An Wang; Thomas N Darling; Joel Moss

doi:10.1016/j.chest.2019.03.040

Circulating Lymphangioleiomyomatosis Tumor Cells With Loss of Heterozygosity in the TSC2 Gene Show Increased Aldehyde Dehydrogenase Activity

Chest. 2019 Aug;156(2):298-307. doi: 10.1016/j.chest.2019.03.040. Epub 2019 Apr 26.

Authors

Affiliations

¹ Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda.
² Flow Cytometry Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda.
³ The Bioinformatics and Computational Biology Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda.
⁴ Department of Dermatology, Uniformed Services University of the Health Sciences, Bethesda, MD.
⁵ Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda. Electronic address: mossj@nhlbi.nih.gov.

Abstract

Background: Lymphangioleiomyomatosis (LAM) is a destructive metastasizing neoplasm of the lung characterized by proliferation of LAM cells in specialized lung nodules. LAM cells are characterized by expression of the prometastatic and cancer-initiating hyaluronan receptor CD44v6, and loss of heterozygosity (LOH) of TSC1 and TSC2. The circulating neoplastic LAM cells are thought to be involved in metastasis. Because LAM cells display properties of neoplastic, metastatic, and stem cell-like cancer cells, we hypothesized that elevated aldehyde dehydrogenase (ALDH) activity, characteristic of cancer and stem cells, is a property of LAM cells.

Methods: We performed an in silico search of ALDH genes in microdissected LAM lung nodules. To identify circulating LAM cells, we osmotically removed red blood cells from whole blood to obtain peripheral blood mononuclear cells, which were then sorted by fluorescence-activated cell sorting based on their level of ALDH activity.

Results: Microdissected LAM lung nodules possess a distinctive ALDH gene profile. The cell subpopulation with high ALDH activity, isolated from circulating cells, possessed TSC2 LOH in 8 of 14 patients with LAM. Approximately 60% of the circulating cells with high ALDH activity expressed CD44v6. Cells with TSC2 LOH from patients with LAM and LAM/TSC exhibited different properties in different body locations, but all cell types showed high ALDH activity.

Conclusions: This new procedure allows for isolation of circulating LAM cells from cultured cells, blood, and chylous effusions and shows that circulating LAM cells are heterogeneous with neoplastic, metastatic, and cancer-stem cell-like properties.

Keywords: biomarkers; circulating tumor cells; loss of heterozygosity; lymphangioleiomyomatosis; tuberous sclerosis complex.

Publication types

Research Support, N.I.H., Intramural

MeSH terms

Aldehyde Dehydrogenase / metabolism*
Humans
Loss of Heterozygosity / genetics*
Lymphangioleiomyomatosis / enzymology*
Lymphangioleiomyomatosis / genetics*
Lymphangioleiomyomatosis / pathology
Neoplastic Cells, Circulating / metabolism*
Tuberous Sclerosis Complex 2 Protein / genetics*

Substances

TSC2 protein, human
Tuberous Sclerosis Complex 2 Protein
Aldehyde Dehydrogenase