Lymphangioleiomyomatosis: A Monogenic Model of Malignancy

Abstract

Lymphangioleiomyomatosis (LAM) is a rare, low-grade, metastasizing neoplasm that arises from an unknown source, spreads via the lymphatics, and targets the lungs. All pulmonary structures become infiltrated with benign-appearing spindle and epithelioid cells (LAM cells) that express smooth-muscle and melanocyte-lineage markers, harbor mTOR-activating mutations in tuberous sclerosis complex (TSC) genes, and recruit abundant stromal cells. Elaboration of lymphangiogenic growth factors and matrix remodeling enzymes by LAM cells enables their access to lymphatic channels and likely drives the cystic lung remodeling that often culminates in respiratory failure. Dysregulated cellular signaling results in a shift from oxidative phosphorylation to glycolysis as the preferred mode of energy generation, to allow for the accumulation of biomass required for cell growth and tolerance of nutrient-poor, anaerobic environments. Symptomatic LAM occurs almost exclusively in females after menarche, highlighting the central but as yet poorly understood role for sex-restricted anatomical structures and/or hormones in disease pathogenesis. LAM is an elegant model of malignancy because biallelic mutations at a single genetic locus confer all features that define cancer upon the LAM cell-metabolic reprogramming and proliferative signals that drive uncontrolled growth and inappropriate migration and invasion, the capacity to exploit the lymphatic circulation as a vehicle for metastasis and access to the lungs, and destruction of remote tissues. The direct benefit of the study of this rare disease has been the rapid identification of an effective FDA-approved therapy, and the collateral benefits have included elucidation of the pivotal roles of mTOR signaling in the regulation of cellular metabolism and the pathogenesis of cancer.

Keywords: lymphangiomyomatosis; perivascular epithelioid cell tumor (PECOMA); tuberous sclerosis; tumor suppressor syndrome.

Figure 1

(a) Schematic representation of the mTOR signaling pathway before discovery of TSC function. (b) Simplified schematic representation of our current understanding of the mTOR signaling pathway. In normal cells, growth factors or insulin (Ins) activate their cognate receptor tyrosine kinases (RTKs), leading to autophosphorylation. Activated RTKs recruit PI3K, a key enzyme that transduces extracellular signaling into cellular responses by activating serine-threonine kinase Akt. Akt phosphorylates TSC (a complex of two proteins, TSC1 and TSC2), releasing the small GTPase Rheb from TSC suppression, which results in activation of mTORC1. In lymphangioleiomyomatosis (LAM), the TSC1/2 complex is mutationally inactivated and does not suppress Rheb. Activated Rheb and amino acids, through the complex composed of Ragulator, RagA/B, and RagC/D, recruit mTORC1 to the lysosomal surface. Constitutively activated mTORC1 induces metabolic reprogramming by (1) upregulating transcription of HIF1α, thereby modulating the expression of glycolytic enzymes, SREBP transcription factors mediating synthesis of fatty acids and cholesterol, and enzymes of the pentose phosphate pathway (PPP); (2) increasing translation of ribosomal and mitochondrial proteins, thereby inducing ribosomal and mitochondrial biogenesis; and (3) inducing de novo synthesis of proteins, lipids, and nucleotides (purines and pyrimidines). STAT3 is required for LAM cell survival, consistent with a role for the mTORC1-STAT3 axis in regulation of prosurvival genes in TSC1/2-deficient cells.