Lupine Publishers | Open Acess Journal Of Oncology and Medicine
Overall tumorigenesis in neurofibromatosis type 1 patients
constitutes a series of specific targeting events with a central role
enacted by proliferation of fibroblasts and endothelial cells in
overproduction of growth factors and cytokines such as transforming
growth factor-beta and CXCL12 cytokine. The plexiform neurofibroma
well-illustrates dimensions of such cooperative participation
within operative fields of the initial Schwann cell proliferation
leading in a significant number of patients to malignant transformation
of the peripheral nerve sheath tumors. Inclusive directions in operative
targeting of Schwann cells or astrocytes are staged
performance in the transformation of hyperproliferative induction and
constitute further evolutionarily defined incorporation of
such systems as endothelial cells. Hyperproliferative cell subsets are
initial and also consequential target formulation of potential
malignant states as induced in malignant peripheral nerve sheath tumors.
Neurofibromatosis type 1 (NF1) is a neurogenetic disorder and
involves both heterozygous and homozygous absence/reduction
of neurofibromin that acts normally as a tumor suppressor.
There is a need to assess predisposing genetic factors and loss
of heterozygosity causing emergence of aggressive neoplasms
in patients with NF1 [1]. The two hit hypothesis helps account
for the emergence of Schwann cell-based proliferations and
for neurofibromas and plexiform neurofibromas. Gherkin may
act on tumorigenesis of cutaneous neurofibromas via growth
hormone secretagogue receptor [2]. It is important to consider the
neurofibroma that is based on micro-environmental potentiation of
tumor generation in patients that develop malignant nerve sheath
tumors and astrocytomas in patients with NF1 +/- genotype;
this occurs in a manner that involves growth factor overactivity
and mast cell and endothelial overactivity within a milieu that
dysfunctionally stimulates tumorigenesis. Reactive oxygen
species overproduction lead to epithelial-mesenchymal transit in
patients with neurofibromin deficiency and plays a crucial role
in NF1 tumor growth [3]. RAS activation alone is not sufficient
for malignant transformation of peripheral nerve sheath tumors;
signal transduction may potentially help identify therapies for this
neoplasm type [4].
The dynamics of neurofibromin as a cytoplasmic protein involve
the regulation of K-Ras, and the PI3K/Akt pathways; absence of
neurofibromin leads to overactivation of these pathways in various
ways in inducing tumorigenesis in such lesions as optic tract
pilocytic astrocytomas, brain stem astrocytomas and also other
CNS astrocytomas in terms of progression of these lesions. The cell
of origin determines the temporal course of neurofibromatosis-1
low-grade glioma formation [5]. The micro-environment of
plexiform neurofibromas of peripheral nerves and of nerve plexi
include a 10% risk of malignant change with subsequent aggressive
clinical behavior in the affected patients. Over expression of cellular
retinoid acid binding protein 2 is reported in several cancer types,
including malignant peripheral nerve sheath tumors (MPNSTs) [6].
The neurofibromin insufficiency status in Schwann cells
and fibroblasts allows for enhanced participation of immune
system component cells such as microglia as evidenced in optic
pathway low-grade astrocytomas. Telomere erosion is described
in many tumor types and may potentially drive genomic
instability and clonal progression in NF1-associated MPNSTs
[7]. Tumor dimensions include proliferation of astrocytic cells
in optic pathways, and of various subtypes of stromal cells such
as fibroblasts and mast cells in the peripheral nervous system. It
is significant to consider particularly the micro-environmental
active participation in the genesis of the most common tumor type
in Neurofibromatosis type 1 patient, that is the neurofibroma,
which invokes proliferation of fibroblasts and endothelial cells.
The congenital plexiform neurofibroma is in fact a hypervascular
lesion that transgresses tissue margins and induces a significant
risk for malignant transformation. NF1 loss is the primary driver
of tumorigenesis in neurofibromatosis type 1-related plexiform
neurofibroma [8]. It is further to such considerations that important
cooperative intervention in malignant transformation of plexiform
neurofibromas invokes multi-type cells in inducing proliferation of
an integral Schwann cell-fibroblastic twin population in enhancing
potential malignant transformation of the peripheral nerve sheath.
A therapeutic window for neuroprotective intervention exists
as detected by optical coherence tomography in mice with optic
glioma, and particularly as an accurate biomarker of retinal ganglion
cell apoptosis [9]. The heterozygous absence of one neurofibromin
allele in mice results in plexiform neurofibromas and low-grade
optic pathway astrocytomas. Mast cells appear to play a causal role
in neurofibroma formation and also in microglia in optic pathway
glioma evolution [10]. Such implications of the micro-enviromental
factors includes a distinctive cooperative participation that carries
implications for significant enhancement of cell proliferation
and of such cytokines such as transforming growth factor and
CXCL12 in formulating malignant transformation in such tumors.
The methylemetetrahydrofolate reductase 1298 and 677 gene
polymorphisms are related to optic glioma and hamartoma risk
in NF1 patients through effects on DNA synthesis and methylation
[11].
The related tuberous sclerosis complex is analogous to
neurofibromatosis type 1 as a neurogenetic disorder associated
with increased risk for astrocytomas in the form of subependymal
giant cell astrocytomas. A convergent targeting of systems of cell
proliferation include in particular cyclic AMP and Ras in a manner
that includes dimensions of micro-environmental conditioning.
Mutations of the NF 1 gene are frequent in many cancer types
in patients without NF1 and this is suggestive of a more general
role for the NF1 gene in oncogenesis. In melanoma NF1 mutations
potentially drive tumorigensis and promote drug resistance [12].
Inclusive dynamics allow for permissive tumorigenesis in a manner
that includes the incorporation of malignant transformation within
confines of a Schwann cell-fibroblast-endothelial cell system in
the case of malignant peripheral nerve sheath tumors. Astrocytes
and microglia are analogous counterparts in the induction of
CNS astrocytomas. Such considerations are inclusive phenomena
of multi-component induction of potential malignancy that recharacterizes
conditioning of the micro-environment of proliferative
states preceding tumorigenesis. Interaction between neoplastic
Schwann cells and their surrounding neural microenvironment
has important implications for early cellular events promoting
tumorigenesis in neurofibroma development [13].
Performance dynamics of tumors in neurofibromatosis type
1 may potentially modify the biologic significance of a two-hit
hypothesis in a manner that implicates micro-environmental
conditioning of the resultant cell hyperplasias and proliferations in
such lesions as peripheral nerve sheath tumors and astrocytomas.
NF1 provides unique vantage points to examine co-contributions
of molecular, cellular, and tissue processes in tumor biology [14].
Such proposed dimensions invoke in particular an over-activation
in production and action of growth factors that provoke selective
malignant transformation of hyper-proliferative lesions composed
of Schwann cells and astrocytes in the peripheral and central
nervous systems respectively. Plasma soluble levels of transforming
growth factor-beta and interleukin-6 are increased in NF1 patients
and a shift towards an anti0inflammatory profile has been reported
in cells expressing cytokines [15].
The hyperproliferative states affecting Schwann cells and
astrocytes invoke also fibroblast and microglial cell proliferations
in a manner transforming tumorigenesis. Such facilitation to
tumorigenesis invokes dimensions of transformation as well
seen in plexiform neurofibromas that may undergo malignant
transformation in a significant number of affected individuals.
Such considerations are selective targeting of specific cell subpopulations
in a manner that allows permissive transformation.
Insertional mutagenesis identifies a STAT3/Arid1b/beta-catenin
pathway that drives neurofibroma initiation in the context of Nf1
loss [16]. Mast cells and fibroblasts may potentially incorporate
endothelial cells that may participate as central dysregulatory
dimensions in plexiform neurofibroma tumorigenesis. The
provocations for malignant transformation further cooperate
in systems of derivative consequence as hypervascular lesions
that subsequently lead to potential malignant cells in individual
patients. Cross species comparative oncogenomic may identify
driver mutations in mouse cancer models and allow validation in
human tumors [17].
Propositional implications in tumorigenesis include the
multi-component participation of Schwann cells on the one hand and of fibroblasts, mast cells, endothelial cells and also of
microglia in an inductive process that includes specific pathways
of malignant transformation. Endothelial cell proliferation is
related to substantial participation in modes related to key-events
of increased proliferation of Schwann cells and astrocytes in initial
stages of lesion infliction. Inclusive phenomena have thus become
systems of consequence in affecting such specific cell proliferative
states. Such events occur within the added dimensions of directed
targeting of multiple-agent micro environmental modeling of the
initial proliferation of the Schwann cells or astrocytes. A pivotal
series of roles played by fibroblasts, endothelial cells, mast cells
and of microglia and astrocytes appears a dynamic milieu within
added consequences of malignant transformation of both Schwann
cells and astrocytes that progress as cooperative systems of
tumorigenesis.
Abstract
Introduction
Neurofibromin
Related Tumor Predispositions
Convergent Targeting
Performance Dynamics
Hyperproliferation
Concluding Remarks
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