Cell Biology in Brain Cancer

Introduction
Cancer has been one of the most devastating ailments in the
contemporary human society. While cancer is composed of more than 100
different ailments, all cancer cells have one crucial characteristic
they are anomalous cell in which the processes that regulate normal
division of cells are disrupted. This underlines the fact that cancer
develops from variations that result in the acquisition of abnormal
functions by normal cells. These alterations and modifications are often
caused by inherited mutations or may be induced by environment factors
including viruses, chemicals, tobacco products, X-rays, or ultra violet
lights among other things (Yang, 2006). Indeed, research has shown that
a large number of cancers do not result from one single factor or event
rather about four to seven would often be required in order for a normal
cell to be modified or evolve via a series or premalignant stages to
become an invasive cancer. In most cases, the evolution of the cancer
cells would take a number of years between the triggering or initial
event and the growth of the cancerous cells (Yang, 2006). Immense
research has been done to determine the varied aspects of cancer, its
risk factors, causes, ways of preventing its occurrence, and especially,
the appropriate cure for cancer.
Recent times have seen an increase in the prevalence of cancer of varied
types including skin cancer, blood cancer, breast cancer, prostate
cancer, cancer of the uterus, as well as cancer that affects the nervous
system. Any type of cancer is undoubtedly devastating especially
considering the rigorous and delicate treatment regimens that would be
given to eliminate it or at least pacify its effects (Yang, 2006).
However, even more devastating and delicate is any type of cancer that
touches on the nervous system, especially considering the fundamental
nature of the nervous system to the health and survival of an
individual. One of the most prevalent types of cancers in the
contemporary human society is Brain cancer.
Brain tumors are characterized as either primary brain tumors or
metastatic brain tumors. Primary brain tumors refer to the types of
brain tumors that start at the brain and tend to remain in the brain.
While this type of brain tumors occurs in individuals of all ages,
statistics show that they are more prevalent in children compared to
older adults. On the other hand, metastatic brain tumors refer to those
brain tumors that start as cancer in other parts of the body before
spreading to the brain. This type occurs more frequently in adults than
in children. Underlining the prevalence of brain cancer is the fact that
brain tumors have been ranked as the second leading causes of deaths
related to cancer in children below the age of 20 after leukemia, and
have occupied the same position in cancer related deaths in males
between the age of 20 and 39 after leukemia (American Brain Tumor
Association, 2013). There have been worrying trends in the prevalence of
brain tumors. In the year 2010, it is estimated that over 688,096
individuals in the United States had been diagnosed with primary brain
tumor (American Brain Tumor Association, 2013). This number was spread
out between non-malignant and malignant tumors with over 550,042 people
having been diagnosed with non-malignant brain tumor while the rest had
malignant brain tumor (American Brain Tumor Association, 2013). On the
same note, it was estimated that for every one hundred individuals in
the United States, about 221 have been diagnosed with brain tumor. This
year alone (2013), researchers have estimated that about 69,720 new
cases of primary brain tumor would be diagnosed including 24,620 and
45,100 malignant and malignant brain tumor cases (American Society of
Clinical Oncology, 2013). Of course there are variations in the
prevalence rates of the varied types of brain cancers including
meningiomas, gliomas, astrocytomas, lymphomas, nerve sheath tumors,
lymphomas, pituitary tumors, and medulloblastomas tumors (American Brain
Tumor Association, 2013). However, a large number of primary tumors are
situated at the meninges (34%), followed by tumors situated in the
temporal, occipital, parietal and frontal lobes of an individual’s
brain (American Brain Tumor Association, 2013).
Like other forms of cancer, brain cancer results from varied molecular
events that undertake a fundamental alteration of the normal
characteristics of cells. The normal systems of control that hinder the
invasion of other tissues and cell overgrowth in cancer cells are
disabled. The modified cells would, therefore, divide and grow even in
the presence of signals that would normally prevent cell growth, in
which case they would not require special signals to trigger the
division and growth of cells (Drevelegas, 2011). In the course of this
cell growth, they would develop entirely new features such as modified
cell structures, production or generation of new enzymes, as well as a
reduction in cell adhesion. The heritable modifications would enable the
cells and their progeny to not only divide, but also grow even when
there are normal cells that would typically hinder the growth of nearby
cells (Kaye, 2001). It is worth noting that these modifications would
allow for the spread of cancer cells, as well as its invasion of other
tissues.
Scientists have noted that the abnormal nature of cancer cells is often
a result pertaining to the protein encoding genes that are responsible
for the regulation of cell division (Kaye, 2001). More genes would
eventually become mutated, thanks to the mutation and abnormal
functioning of genes that generate the genes responsible for the repair
of damage of DNA. These mutations start increasing in the cell, as a
consequence, thereby resulting in more abnormalities both in the
specific cell and even the daughter cells (Drevelegas, 2011). It is
worth noting that while a number of the mutated cells die, some of the
modifications may, in fact, give them selective advantage that enables
them to multiply at a faster rate than the normal cells. The improved
rate of growth underlines a large number of cancer cells that have
obtained functions that are repressed in healthy or normal cells. In
instances where the cells remain at their original location, they would
be considered benign, while they would be considered malignant in cases
where they become invasive. In cases where the cancer cells are in the
malignant tumors, they usually metastasize and send cancer cells to
other parts of the body, in which new tumors would eventually develop.
This is the case for metastasized brain tumor.
Genetics of cancer
Cancer has only been associated with a small number of the about 35000
genes in human genome. In most cases, modifications in this gene usually
relate to varied forms of cancer. The malfunctioning genes are
categorized in three groups including proto-oncogenes, tumor
suppressors, and the group containing DNA repair genes. Proto-oncogenes
are responsible for the production of protein products that usually
prevent the death of normal cells or improve cell division. Their
mutated forms are referred to as oncogenes (Freedman, 2009). Tumor
suppressors, on the other hand, are responsible for the making of
proteins that ordinarily prevent the division of cells and cause the
death of normal cells. The category containing DNA repair genes is
responsible for the prevention of mutations that could result in cancer
(Clark, 2006). This categorization underlines the fact that the
controlled growth of the cell would be maintained by the control of
proto-oncogenes that are responsible for the acceleration of growth,
alongside tumor suppressor genes that are responsible for the slowing
down of the growth of cells (Clark, 2006). Any mutation that results in
the production of oncogenes would fasten growth while a mutation that
affects tumor suppressors would hinder the normal prevention of growth.
Either way, there would be uncontrolled growth of cells.
In normal cells, proto-oncogenes are responsible for coding for
proteins that send signals to the cell nucleus so as to trigger division
of cells. The signaling proteins function in varied steps referred to as
signal transduction pathway or cascade, which is made up of membrane
receptor for the signal molecule, the intermediary proteins that are
responsible for the transmission of the signal via the cytoplasm, as
well as the transcription factors situated in the nucleus that would
activate the genes for the division of cells (Booth, 2004). In every
stage of the cascade, a single protein or factor would activate the
next. It is worth noting, however, that some factors may have the
capacity to activate two or more proteins in the cell. The altered
versions of proto-oncogenes are referred to as oncogenes, which are
responsible for the coding of the signaling molecules (Ali-Osman, 2005).
Oncogenes would persistently activate or stimulate the signaling
cascade, leading to enhanced generation of factors that would trigger
growth. The modification or alteration of proto-oncogenes to oncogenes
may be caused by mutation, increased number of copies of normal
proto-oncogenes, or even rearrangement of genes in chromosomes transfers
the proto-oncogenes to new locations. In some cases, viruses would
insert their DNA close to or near the proto-oncogenes thereby triggering
their conversion to oncogenes (Freedman, 2009). These events would
result in the modified form of genes thereby contributing to cancer. In
this case, mutations that alter proto-oncogenes into oncogenes would
result in uncontrolled cell growth. A large number of oncogenes are
essentially dominant mutations, where one copy of this gene would be
sufficient to express the growth trait (Ali-Osman, 2005). This would
also be characterized as a gain of function mutation as the cells that
have mutant protein forms would have an additional function that is not
present in cells that have normal genes. It is worth noting that the
presence of oncogenes in eggs or sperms would cause an inherited
predisposition for tumors in an individual’s offspring (Yang, 2006b).
Mutations in tumor suppressor genes, on the other hand, would result in
cells that do not exhibit normal inhibition of the division and growth
of cells. Products of tumor suppressor genes can act in the nucleus,
cytoplasm or even at the cell membrane (Zeltzer, 2004). In cases where
these cells mutate, they would lose their capacity to hinder the growth
of cells, which means they would often be recessive (Booth, 2004). This
means that there would be no expression of the trait unless both copies
of normal genes undergo mutation. It is worth noting that the two copies
would undergo mutation in cases where the sperm or egg are already
mutated, thereby passing the mutation to all the cells of the offspring
(Prayson, 2009). Further mutation would occur on the gene’s second
copy, which results in the development of uncontrolled growth in the
cell.
In the case of DNA repair genes, DNA may be damaged by environmental
factors such as ultraviolet light, chemicals and asionizing radiation.
The damage to chromosomes would be repaired by certain gene products
thereby lowering cell mutations (Morantz & Walsh, 1994). However, in
instances where DNA repair genes have been mutated, their product would
no longer be made, in which case DNA repair would be prevented while
further mutations would accumulate in the cell (Zeltzer, 2004). These
mutations have the capacity to increase the frequency of the cancerous
modifications or alterations in a cell (Ali-Osman, 2005). For instance,
defects in the DNA repair gene referred to as Xeroderma pigmentosum
would result in individuals that are extremely sensitive to ultraviolet
light, and is known to cause an immense increase in the incidence or
every other type of skin cancer.
Stem cells and Brain cancer
However, cancer stem cells do not amount to simple sets of homogenous
neoplastic cells, rather tumors refer to organ systems that are composed
of neoplastic compartments that have associated vasculature, reactive
extracellular and cellular components, as well as inflammatory cells
(Hayat, 2010). In the early 201th century, brain cancer was recognized
as showing striking morphologic variations underlined by the phrase
glioblastoma multiforme (Morantz & Walsh, 1994). In most cases, glial
tumors incorporate blended subpopulations that bear morphological
resemblance to oligodendrocytes and astrocytes, resulting in the
intermediate diagnosis of the oligoastrocytomas (Zeppernick et al,
2008). In addition, genetic analysis shows that there exists variations
in the gene expressions and chromosomal aberrations in different regions
in a tumor (Morantz & Walsh, 1994). It is worth noting that the regional
differences would also be seen in commonly observed mixed clinical
responses that are detected in specific therapies. In such cases, some
parts of the tumor would respond to the therapy while other areas of the
same tumor would not respond. Scholars note that there have been
evaluations of differentiation markers in human brain tumors and show
that multiple and aberrant differentiation can exist in the same tumor
(Ali-Osman, 2005).
Recent years have seen a dramatic increase in the comprehension of the
normal nervous system development (Adesina, 2010). The nervous system
comes with a complex differentiation hierarchy that ranges from
lineage-committed progenitors that come with a considerably restricted
potential to even terminally differentiated cells and neural stem cells
that have the capacity to produce all the key lineages pertaining to
brain parenchyma (Kirsch, 2004).
Brain tumor stem cells
Scholars are yet to agree on the definition of normal stem cells apart
from the differentiation potential and long-term renewal. In this case,
it is not surprising that there is yet to be any consensus on the
characteristics that define cancer stem cells (Hayat, 2010). Current
definitions pertaining to cancer stem cells necessitate tumor initiation
or propagation, sustained proliferation, as well as self-renewal (Cook &
Freedman, 2012). A number of investigators have chosen nomenclature as
representative for the capacity of cells to propagate tumors, thanks to
the fact that the definition of stem-cell-like populations takes place
in functional assays or evaluations (Kirsch, 2004).
Normal stem cells, more often than not, show specific antigens that all
for prospective enrichment of cells that meet the stem cell criteria.
However, no antigenic profile represents stem cells (Cook & Freedman,
2012). This means that researchers doo not have the capacity to
undertake a direct assessment of the creation of perfect cell copy in
real time. Instead, stem cell evaluations validate that stem cells that
have the capacity for self-renewal must have been in the earlier stages
(Prayson, 2009).
Stem cells come with developmentally regulated replication that may
either be asymmetric or symmetric in response to external cues and the
cell state. Symmetric replication would occur in instances where the
stem cells produce two identical cells, which can either be two
differentiated daughter cells or even two identical cells (Adesina,
2010). Asymmetric replication occurs in instances where the stem cells
replicate to produce one differentiated daughter cell and another one
that is not differentiated.
While there is no standard definition of stem cells in brain tumors,
the gold standard for the definition of normal adult stem cells has
remained the production of the entire cellular components pertaining to
the relevant organs from single stem cells. In the case of the nervous
system, the capacity for the formation on of astrocytes, neurons, and
oligodendrocytes is necessary in normal neural stem cells (Goldman &
Turner, 2009). Indeed, the differentiation cascade pertaining to the
hermatopoietic systems is the best characterized by far, although the
nervous system is considerably well modeled.
An examination of the Role of Brain Tumor Stem Cells in Angiogenesis and
Therapeutic Resistance
Malignant gliomas are usually angiogenic, with vascular proliferation
coming as a histologic feature showing a glioblastoma among gloiomas.
Malignant gliomas produce or secrete a large number of growth factors so
as to stimulate, as well as maintain neoangiogenic structure (Adesina,
2010). Scientists have come up with targeted therapies against a number
of these pathways, with a large number of clinical trials showing modest
benefits from the agents. However, there has been noted potential
clinical efficacy in Avastin (a neutralizing antibody) trials against
VEGF (Morantz & Walsh, 1994). It is interesting to note that there has
been modest activity pertaining to low-molecular-weight inhibitors
against VEGF receptors in clinical trials, which shows that different
agents may target similar molecular pathways with different outcomes
(Cook & Freedman, 2012). Studies on brain tumor stem cells show that
cancer stem cells develop highly angiogenic tumors in comparison to the
uncommon tumors identified in cancer stem cells-depleted cultures. It
was found that conditioned media derived from cancer stem cells would
strongly induce endothelial cell migration, as well as proliferation and
tube formation when contrasted with nonstem cancer cell conditioned
media (Black, 2006). Bevacizumab, in animal studies, has been found to
strongly cause a reduction in the growth of tumors obtained from cancer
cells to a paucity and size of vascularity that is closely similar to
that of uncommon tumors generated by non-stem cancer stem cells (Cook &
Freedman, 2012). Angiogenic drive may offer an explanation as to the
striking tumor propagation in cancer stem cells considering that
non-stem cancer cells have the capacity to survive implantation while
rarely forming tumors (Ali-Osman, 2005). On the same note, cancer stem
cells may offer an angiogenic drive to prop up the growth and
development of non-stem cancer stem cells, which shows that their impact
or effects on the tumor may not require to be solely restricted to the
direct production of progeny (Goldman & Turner, 2009). Scientists have
also noted that stem cancer cells are situated close to vasculature, as
confirmed by studies that show that the growth of brain tumor stem cells
is supported or propped up by endothelial cells, as well as the fact
that the formation of a tumor by cancer stem cells needs the support of
a vascular niche (Ali-Osman, 2005). Indeed, other studies have indicated
that the cancer stem cell marker-positive cells are situated in
perivascular niches (Black, 2006). These observations underline the fact
that brain tumor stem cells are capable of forming their own tumor
microenvironment via elaborating angiogenic factors while remaining
autonomous from the niche (Adesina, 2010). This may partially explain
the clinical activity pertaining to bevacizumb, as well as the invasive
phenotype in individuals that suffer failure after being treated with
bevacizumb as cancer stem cells show an invasive phenotype.
With regard to therapeutic resistance, it is unfortunate that patients
that have malignant gliomas usually suffer failure of treatment and
death (Banerjea, 2002). Cytotoxic modalities (such as chemotherapy and
radiation) and surgical resection have remained the core or foundation
of brain tumor therapy. It is worth noting that the techniques through
which brain tumors attain resistance to conventional or traditional
therapies are potentially multifactorial and are poorly comprehended
(Black, 2006). An examination of the likely contribution that brain
tumor stem cells make to the resistance of brain cancer to radiation has
shown that the ionizing radiation would cause an increase in the
relative frequency pertaining to the tumor cells showing cancer stem
cell markers in the treated xenografts (Banerjea, 2002). It is worth
noting that maintained ability for tumor propagation and self renewal
accompanied these cells relative enrichment, while similar or matched
non stem cells had a higher likelihood of dying. Of particular note is
the fact that cancer stem cells-enriched cultures, when treated using
radiation, exhibit lower apoptotic fraction compared to nonstem cells in
similar conditions, thereby enabling the cancer stem cells to be
outgrown (Liau, 2001). When treated with radio-mimetics or radiation,
cancer stem cells have exhibited an enhanced activation of the
DNA-damage checkpoint response as compared to that of similar nonstem
cancer cells. As much as studied have shown variations among samples, a
number of proteins seem to be activated at baseline as if the cancer
stem cells had been prepared to react to or counter genetic stress that
may, essentially, be an early occurrence in the initiation of cancer
(Cook & Freedman, 2012). Nevertheless, the role of the response of
DNA-damage checkpoint should to have a contribution to the resistance of
brain tumor cells to radiation as the pharmacological inhibitor
pertaining to the checkpoint would make the cancer stem cells sensitive
to radiation (Goldman & Turner, 2009). Other studies have also shown
that neurosphere-forming brain tumor cells have a considerably higher
resistance to chemotherapy compared to similar cells that are grown in
differentiating conditions (Zeltzer, 2004). However, as much as a large
number of studies shown that cancer stem cells may be responsible for
the common therapeutic resistance shown by brain tumors, and may even be
targeted in pharmacological responses, scholars have underlined the fact
that it is highly unlikely that cancer stem cells are wholly responsible
for the full extent of resistance noticed in brain tumors.
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