No consistent metabolic model currently exists for LAM, therefore wild-type mouse embryonic fibroblasts (MEF +/+) and TSC2 knockout cells (MEF -/-) were used in this study as a model for LAM.
In previous work we found loss of heterozygosity (LOH) of the wild-type TSC2 allele in the abnormal pulmonary smooth muscle cells and renal angiomyolipoma cells from patients with sporadic pulmonary lymphangiomyomatosis (LAM).
These data demonstrate that tuberin negatively regulates the activity of S6 and p70S6K specifically, and suggest a potential mechanism for abnormal cell growth in LAM.
Isolated pulmonary LAM cells have been difficult to maintain in culture, and most studies of LAM lung cells involve mixtures of TSC2 wild-type and TSC2-null cells.
Recent studies, however, revealed that both forms of LAM are genetically related but that sporadic LAM is a distinct clinical entity caused by somatic mutations of TSC2 (not TSC1) rather than a forme fruste of TSC carrying either of the TSC1 or TSC2 germline mutations.
The origin of LAM cells remains unknown; however, inactivation of Tsc2 gene in the mouse uterus resulted in myometrial tumors exhibiting LAM features, and approximately 50% of animals developed metastatic myometrial lung tumors.
Using a LAM patient-derived cell line (bearing biallelic Tuberin inactivation), we demonstrate that E2 stimulates a robust and biphasic activation of ERK2 and transcription of the late response-gene Fra1 associated with epithelial-to-mesenchymal transition.
Proliferation of LAM/TSC cells is epidermal growth factor (EGF)-dependent and blockade of EGF receptor causes cell death as we previously showed in cells lacking tuberin.
To investigate whether these lipids are generated in a TSC2-dependent manner, we profiled in vitro preclinical models of TSC/LAM and found significant LPC accumulation in TSC2-deficient cells relative to TSC2-expressing control cells.
In the present study, it was revealed that miR‑124 was downregulated in LAM specimens and overexpression of miR‑124 resulted in the apoptosis of TSC2‑deficient cells via RXRα (retinoid X receptor α), while slightly influencing TSC2 wild‑type cells.
The tumor suppressor genes TSC1 and TSC2 have been implicated in the etiology of LAM, as mutations and loss of heterozygosity (LOH) in TSC2 have been detected in LAM cells.
Simvastatin, but not atorvastatin, showed a concentration-dependent (0.5-10 μM) inhibitory effect on mouse TSC2-null and human LAM-derived cell growth.
Urotensin receptor antagonists may be selective therapeutic agents for the treatment of LAM or other neural crest-derived neoplasms featuring loss of TSC2 or increased expression of the urotensin receptor.
We hypothesized that these cellular mechanisms of OPG may be involved in the growth and proliferation of lymphangioleiomyomatosis (LAM) cells, abnormal smooth muscle-like cells with mutations in one of the tuberous sclerosis complex tumor-suppressor genes (TSC1/TSC2) that cause LAM, a multisystem disease characterized by cystic lung destruction, lymphatic infiltration, and abdominal tumors.
Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM.
While the lymphatic system has been implicated in TSC through lymphangioleiomyomatosis (LAM) and lymphedema, this paper reports the first case of PIL in TSC, a female patient with a TSC2 mutation.
We describe herein a TSC2-harboring tuberous sclerosis patient manifesting with a synchronous well-differentiated L-cell rectal neuroendocrine tumor and leiomyomatosis-like LAM of the rectum.