Developmental Abnormalities and Cancer Predisposition in Neurofibromatosis Type 1

Abstract

Neurofibromatosis type 1 (NF1) is a developmental and cancer predisposing syndrome resulting from haploinsufficiency or alteration in neurofibromin, a multifunctional protein that acts in various signaling pathways affecting morphogenetic processes and cell proliferation. Neurofibromin deficiency deregulates Ras/Raf/MEK/ERK and Ras/PI3K/AKT/PKB/mTOR signaling networks and intersected pathways including the cAMP-dependent protein kinase A (PKA) and the Rho-cofillin which acts on actin cytoskeleton reorganization, cell motility and adhesion. As the neurofibromin-mediated pathways are associated with biological effects depending on the cell lineage, deregulation induced by NF1 mutation clearly has cell type-specific effects. This review summarizes our increasing knowledge of NF1 as a disease rooted in defective developmental mechanisms that can also influence the potential for malignant growth. The cardinal features of NF1 patients, at birth and during life involve the cardiovascular, connective/skeletal and central nervous systems, as they reflect the NF1 mutation sensitivity of cell lineages committed to specifying these systems during embryonic development. A switch to neoplastic transformation may also occur in both the prenatal and postnatal life in cancer initiating cells of defined lineages, with the cooperation of a genetically and epigenetically modified tumor microenvironment. We emphasize how much of our current knowledge of the pathomechanisms of NF1 clinical signs and cancer has come from engineered mouse models and in vitro primary cells and cell lines exposed to inhibitors of signaling molecules. Advances in our knowledge of the developmental defects primed by the loss neurofibromin should reveal further associations between given NF1 mutations and tissue-specific symptoms, thus improving the clinical management of the patients.

GENETICS IN ENDOCRINOLOGY: The genetics of phaeochromocytoma: using clinical features to guide genetic testing

“…Cutaneous (localised and plexiform neurofibromas, neurofibrosarcoma) and internal tumours such as aPCA/eFPGL, central nervous system tumours (glioma, astrocytoma and optic gliomas), carcinoid and leukaemia may occur (15). Although NF1 is relatively common (incidence one in 3000 persons), the prevalence of aPCA/eFPGL in NF1 is low (w1%).…”

Mechanical Signaling in NF1 Osteoblast Cells

“…The NF1 gene encodes neurofibromin, a RAS GTPase-activating protein (GAP) that promotes the conversion of an active RAS-GTP-bound form to an inactive RAS-GDP form and functions to negatively regulate the activity of RAS effectors, including the RAF-MEK-ERK signaling pathway [8,9]. Thus, NF1 mutations results in activation of canonical mitogenactivated protein kinase (MAPK) signaling [10,11]. Of relevance to skeletal development, NF1 expression has been reported in hypertrophic chondrocytes, which are an important intermediate step during endochondral ossification, and also in adult osteoblast and osteoclasts [12,13] either of which might explain the skeletal involvement in NF1.…”

Hiding in Plain Sight: A Consideration of NF1-Associated Hypovitaminosis D and its Treatment

“…They include both congenital heart disease and cardiomyopathy and several types of developmental vascular dyscrasias, most often involving the carotid-vertebral-brachial artery complex, the renal arteries, the superior mesenteric artery and the mid-portion of the aorta. In particular, there is nothing we know about the NF1 gene locus per se [8] to suggest or explain abnormalities of vitamin D metabolism. Certainly, the most intensely studied NF1 domain-the GAP-related domain, or GRD-provides no intrinsic clue.…”