An intelligent design aimed at preventing distant metastasis in females.

We describe here an integrated, conserved function for gene programs broadly governed by tumor suppressors in protection against metastasis to the major distant organ sites in females: the brain (central nervous system, or CNS), the liver and the lungs. We recently pioneered the concept of evasion of immunosurveillance through targeted tumor activation of tissue-restricted antigen to signal “self”. We described a liver-specific function for the hepatic developmental regulator Hnf4a in TRA activation in oncogenic contexts involving primary or metastatic tumor survival in the liver. Here, we demonstrate in the lungs, and in tissues outside of the respiratory system, as recently described for hepatic TRA, activation of multiple surfactant proteins including SFTPA2 and SFPTD that functioned to enhance engraftment and survival following homing to the distant organ site, indicating the presence of a on-going evolutionary conflict based in transformation in the female. 

This mechanism of tumor modification of self non-self discrimination for evasion of general and anti-tumor surveillance is an apparently essential mechanism engaged by the tumor, occurs through activation of canonical TRA like AIRE, induction of novel autoimmune regulators with organ-specific TRA potential, and a third mechanism of specific gene product modulation for organ-selective and general immune evasion associated with a protective effect against distant metastasis whose associated nuclear factor could not be discerned. Each of these mechanisms was extra-thymic. In a separate manuscript, we present evidence for endogenous restriction of CNS malignancy in humans that combined the function of cellular gene products lacking any immune function functioning by cell-intrinsic transformation control, traditional innate immune mechanisms involving Ig- and LRR-containing immune receptors, and a pathway involving CNS immunologic privilege controlled by a specific interferon system receptor found only in higher vertebrates. In a second manuscript, we present evidence demonstrating that a basic function of innate immune receptors of the NLR family was sensing and control of excess neuropeptide, neurohormone and sex hormone expression. Together, we demonstrate the presence of a highly evolved system that combines cell-intrinsic and cell-extrinsic mechanisms derived from the hematopoietic system and tissues of each of the organ systems which are preferred sites of metastasis in the population in the female sex. Organization of a multi-system metastasis control program indicated convincingly that its origins could be found in a design and intent to protect the female from naturally occurring transformation (cancer).