Pulmonary lymphangioleiomyomatosis: A proposed state of neoplastic senescence

Pulmonary lymphangioleiomyomatosis (PLAM) is a disease strongly associated with tuberous sclerosis. In PLAM patients, with and without clinical tuberous sclerosis, mutations in the tuberous sclerosis complex involving the proteins hamartin and tuberin have been found. These proteins are key regulators of the mTOR pathway. mTOR activation is a key step in normal cellular senescence. The hypothesis proposed here is that mutations in the tuberous sclerosis complex leading to mTOR activation result in the specialized LAM cells acquiring many of the cellular characteristics of the normal senescent cell, a state that I propose to characterize as a state of neoplastic senescence. Using this hypothesis as a theoretical basis, many of the enigmatic features of the pathogenesis and clinical behavior of PLAM can be explained. In addition, the hypothesis may lead to new insights into possible therapeutic interventions for this disease.