mTOR activation, lymphangiogenesis, and estrogen-mediated cell survival: the "perfect storm" of pro-metastatic factors in LAM pathogenesis

Abstract

Research interest in lymphangioleiomyomatosis (LAM) has grown dramatically in the past decade, particularly among cancer biologists. There are at least two reasons for this: first, the discovery in the year 2000 that LAM cells carry TSC2 gene mutations, linking LAM with cellular pathways including the PI3K/Akt/mTOR axis, and allowing the Tuberous Sclerosis Complex (TSC)-regulated pathways that are believed to underlie LAM pathogenesis to be studied in cells, yeast, Drosophila, and mice. A second reason for the rising interest in LAM is the discovery that LAM cells can travel to the lung, including repopulating a donor lung after lung transplantation, despite the fact that LAM cells are histologically benign. This "benign metastasis" underpinning suggests that elucidating LAM pathogenesis will unlock a set of fundamental mechanisms that underlie metastatic potential in the context of a cell that has not yet undergone malignant transformation. Here, we will outline the data supporting the metastatic model of LAM, consider the biochemical and cellular mechanisms that may enable LAM cells to metastasize, including both cell autonomous and non-cell autonomous factors, and highlight a mouse model in which estrogen promotes the metastasis and survival of TSC2-deficient cells in a MEK-dependent manner. We propose a multistep model of LAM cell metastasis that highlights multiple opportunities for therapeutic intervention. Taken together, the metastatic behavior of LAM cells and the involvement of tumor-related signaling pathways lead to optimism that cancer-related paradigms for diagnosis, staging, and therapy will lead to therapeutic breakthroughs for women living with LAM.

FIG. 1.

Estrogen promotes the lung colonization of Tsc2-null ELT3 cells. Female ovariectomized CB17-SCID mice were implanted with estradiol (E₂) (n = 3) or placebo (n = 3) pellets (2.5 mg, 90-day release) one week prior to cell injection. 2 × 10⁵ ELT3-luciferase cells were injected intravenously. Lung colonization was measured using bioluminescence at 1, 3, and 24 h after injection. (A) Representative images are shown. (B) Total photon flux/second present in the chest regions was quantified and compared between E₂ and placebo-treated animals. At 1 h, the bioluminescence in the chest region was similar. By 3 h, the photon flux in the chest region was 2-fold higher in the E₂-treated mice, and by 24 h it was 5-fold higher. *p = 0.05, Student's t test. (C) Lungs were dissected 24 h post-cell injection and bioluminescence was imaged in Petri dishes. From Yu et al. (38).

FIG. 2.

Multistep model of lymphatic-mediated and estrogen-promoted metastasis of LAM progenitor cells. Genetic studies indicate that LAM progenitor cells carrying TSC1 or TSC2 mutations metastasize to lymph nodes, kidneys, and lungs. Collective studies suggest that LAM cell metastasis is driven by several distinct cellular and molecular mechanisms. We propose a multistep model of lymphatic and estrogen-associated metastais. Step 1: LAM-progenitor cells secrete VEGF-D and recruit lymphatic endothelial cells. Step 2: Estrogen induces expression and activity of matrix metalloproteinases (MMPs) to degrade the extracellular matrix (ECM) facilitating invasion. Step 3: LAM cells enter the lymphatic vessels in clusters covered by lymphatic endothelial cells. Step 4: Estrogen enhances the survival of LAM cells in circulation. Step 5: Metastatic lesions develop in distant organs including lungs, kidney. and lymph nodes.