Name: Cornell, Fatmah Sarah M.

Section: NSG 125 | TBA

The Phases of Cell Cycle

One or more cells make up all living organisms. Cells that function together are found in many
multicellular organisms. Working together as part of body tissue and body tissues working
together as part of an organ which the organs working together as part of an organ system. Skin
cells, stomach cells, and muscle cells are all specialized to work at different levels of
organization, and their functions must be regulated. These cells are controlled by a process
known as the cell cycle. And cells have the ability to expand in size. The size of each individual
cell in a multicellular organism does not cause it to increase. Cell reproduction allows a
multicellular creature to develop by producing more cells. You can generate new body cells
through mitosis and the cytokinesis that follows, which splits the cytoplasm, but you don't want
it to happen all the time. Due to the fact that “cancer" is likely to occur.

Cells that divide too quickly are a contributing factor in cancer. The cells are uncontrollable
because they are not regulated. Other issues that cancer cells may face include their inability to
communicate with other healthy cells, their inability to perform regular cell duties, and their
inability to properly anchor themselves as other cells do, making them more prone to go
elsewhere. Cancer cells can produce their own growth hormone. This causes blood arteries to
redirect to the cancer cells, supplying them with nourishment while depriving healthy cells of
nutrients. Some cancers may have genetic connections that make some cells more vulnerable
to problems, these genetic issues may run in families as well as exposure to chemicals,
radiation, or excessive UV light, which can all be risk factors for some cells becoming malignant.
Cancer cells' uncontrolled growth has resulted in the proliferation of similar cells, which can
lead to the formation of a tumor. Some tumors remain in place, while others do not.

The cell cycle is often represented as a pie chart. Cells are either in one of two different phases:
a phase called interphase where the cells themselves are growing, replicating their DNA, doing
their cell functions---- or they are in M phase which includes mitosis and the actual splitting of
the cytoplasm - cytokinesis. So, this M phase is where cells actually divide to make more cells.
But cells spend most of their time in interphase. So, most of the time, they’re not dividing. Now,
depending on what kind of cell, it might do mitosis more or less often; for example, your hair
follicle cells do mitosis frequently which is why your hair can grow at the rate that it does. It’s
also why many cancer drugs may also target hair follicle cells, because many cancer drugs go
after cells that do cell division frequently. It’s a big deal for cells to hit this M phase. If a cell has
an error---a harmful mutation for example---you do not want it to divide because then it will
create another cell that has this same issue (harmful mutation). That’s where check points take
over. Along the cell cycle there are check points to check that the cell is growing well and
replicating its DNA correctly and doing everything it’s supposed to correctly before it divides. To
better understand those checkpoints, let’s further divide this cell cycle pie chart. We have G1
(Gap1), S (synthesis), G2 (Gap2)---all three of those are part of interphase. Then we have M
phase where mitosis will happen. During G1, the cell individually itself grows. Then it replicates
its DNA in S phase…you can remember that because the "s" is for “synthesis” which means to
make something, and it’s making DNA. Then G2, the cell grows some more in preparation for
mitosis.

So let’s take a look at checkpoints. In G1---this checkpoint checks, “Is the cell growing well
enough?’ or “Is its DNA damaged?” while the S phase is where the DNA replicate. Or Does the
cell have the resources it needs. Next is the checkpoint in G2 which checks if the DNA was
replicated correctly back in S phase. Is it growing well enough---does it have the resources it
needs to continue? moving on the next checkpoint. In M phase it checks in the stage
metaphase to make sure that chromosomes, which are made up of DNA, are lined up in the
middle correctly---that they’re all attached to the spindle correctly. Because if they’re not, the
chromosomes will not be separated correctly. If the reason the cell can’t go past the checkpoint
is a reason that can be fixed, the cell may kind of pause here until it can fix the issue. But if it
can’t be fixed? Then the cell does something called apoptosis which basically means the cell
self-destructs. This ensures that a cell that is damaged beyond repair will not go on to divide.

Genes in our body can code for proteins that do an assortment of functions, and there are
many proteins involved with regulating the cell cycle. Some of them are positive regulators
because they allow moving forward in the cycle and some are negative regulators that may
make things stop. The proteins themselves can be sensitive to cues inside and outside of the
cell. There are some cells that don’t go through the phases we mentioned, because they’re
actually in G0. G0 is a resting phase. Now cells here are still performing cell functions, but
they’re not preparing to divide. Some cells go here temporarily, maybe if there’s not enough
resources around for example. But some---like many types of neurons in your brain and spinal
cord may stay here permanently. If they stay here permanently, they’ll never get to M phase so
they will not divide. This can be one reason why a major injury to the brain or spinal cord can
have challenges with healing as many of those cells may not be able to replicate.

Introduction to Cancer

abnormal signal transduction resulting in uncontrolled cell proliferation. loss of apoptosis or

programmed cell death, tissue invasion and metastasis permitting spread of the cancer and angiogenesis
leading to enhanced blood supply of tumors. normal cells require signals usually delivered by ligands to
stimulate their growth and to tell them when to stop growing, these signals or ligands can be in the form
of growth factors and inhibitors. extracellular matrix components or cell adhesion molecules. these
signals are transmitted into the cell through proteins found on the surface of cells called receptors, each
ligand binds to its own specific receptor.

receptors often consist of three domains an extracellular ligand binding domain, a transmembrane
domain and an intracellular domain. binding of a ligand to the extracellular domain activates the
receptor tyrosine kinase which activates other proteins by phosphorylation of adding a phosphate to the
amino acid tyrosine on a protein inside the cell. when a ligand binds to the receptor a signal goes to the
intracellular domain activating the Associated enzyme and initiating a cascade of signals to the nucleus
that tell the cell to grow and divide or to stop growing.

malignant cells generate many of their own growth signals which allows them to divide with reduced
external growth stimulation. some cells are able to produce their own growth factors and stimulate
their own growth, this is called autocrine stimulation. for example glioblastoma is express platelet
derived growth factor or PDGF. sarcomas express tumor growth factor alpha or TGF alpha as well as
epidermal growth factor receptor or EGFR. in normal cells the production of cell surface receptors is
limited by cellular restraints on gene expression and protein translation. in tumour cells however
mutations in the genes encoding for the receptors disrupts this finely tuned regulation and too many
copies of the gene are produced a phenomenon called gene amplification, this in turn leads to excessive
transcription and production of receptors. the end result is a higher than normal number of copies
known as over expression of the receptor on the tumor cell surface. this gives the tumor cell increased
potential to be triggered into a growth phase by the binding of ligands to the excess receptors. the
more receptors expressed, the more binding sites are available for the ligands, gross over expression of
growth factor receptors can result in ligand independent signaling, where receptors are active in the
absence of stimulating molecules. structural changes to a receptor can also lead to ligand independent
activation, for example truncated versions of the epidermal growth factor receptor where much of the
intracellular domain is missing, are constituent 'lay active.

EGF receptor also known as her 1 or herb 1 is a member of a subfamily of type 1 receptor tyrosine
kinases these receptors are found primarily in the membranes of normal epithelial cells from skin,
breast, colon and lung. amongst others. EGF receptor and its ligands play an essential role in the
regulation of cell proliferation, differentiation and survival.

EGFR is overexpressed in tumors arising from the colon, rectum, and had a neck. when a specific ligand
binds to its receptor this leads to changes in the receptor that transmit a specific signal into the cell, for
example the receptor tyrosine kinase is activated and initiates a signaling pathway specific to that
receptor this phenomenon is called signal transduction. activation of a signal transduction pathway
creates a complex chain of events in the cytoplasm or fluid intracellular space that eventually leads into
the cell nucleus, where the transcription of genes regulating cell cycle progression are stimulated.
resulting in cell proliferation one of the major Cascades implicated in cancers is the rats raff mitogen-
activated protein or map kinase pathway. another interesting pathway is the phosphors Anozie tied 3
kinase or pi3k a kt mammalian target of rapamycin or mTOR pathway, these pathways are linked to each
other and other signal transduction pathways in the cell. deregulation or loss of normal controls in any
of these pathways is thought to be present in all human tumors. once the signal reaches the nucleus,
transcription factors are activated, these factors transcribe the genes that are translated into the
proteins such as growth factors that are necessary to allow the cell to continue to proliferate. the end
result of any growth factor receptor signal transduction pathway is tumor DNA replication and cell
division. one tumor cell becomes 2 , if mitosis continues to tumor cells become 4 with exponential
growth potential. on the tissue level this leads to increased tumor growth and increase tumor size.
many of the components of these signal transduction pathways are potential targets of anti-cancer
therapies. therapies can target the ligands, receptors, intracellular second messengers, and nuclear
transcription. factors responsible for tumor growth. ligands can be neutralized before they bind to the
receptors, an example of this is bevacizumab or Avastin which is a humanized monoclonal antibody that
targets circulating vascular endothelial growth factor or vag F. platelet derived growth factor or PDGF
and fibroblast growth factor or fgf are other examples of ligands that can be targeted for different cells
in the body. the receptors on the surface of normal and tumor cells can be inhibited directly. Sutekh
Samad or Erbitux is an example of this, it is a chimeric antibody that binds directly to the epidermal
growth factor receptor and competitively inhibits the binding of EGF and other ligands such as TGF
alpha. another way to block the receptors function is through small molecule inhibitors of receptor
phosphorylation associated with them, for example EGF receptors have a tyrosine kinase that can be
blocked by the molecules gefitinib or ERISA and erlotinib or Tarceva.

apoptosis or programmed cell death is one of the mechanisms by which organisms limit the growth and
replication of cells. if apoptosis did not occur there would be no way to control cell growth and tissue
homeostasis would be lost. in fact this is one of the key mechanisms behind cancer. the genetic
alterations in the cancer cell not only lead to increased cellular proliferation and growth, they also lead
to loss of apoptosis. along with too much cell growth there is too little cell death in malignant tissue.
apoptosis occurs in normal cells to allow for removal of damaged cells, maintain a constant number of
cells in regenerating tissues and is an important part of embryogenesis. the average human adult 50 to
70 billion cells undergo apoptosis per day. apoptosis is characterized by changes such as cell shrinkage.
mitochondrial cytochrome C release. fragmentation of cell DNA into multiples of 180 base pairs, and
the ultimate breakage of cells in too small a pop tonic bodies which will be cleared through
phagocytosis. Phagocytosis is a process where cells take in cell fragments or microorganisms in
membrane-bound vesicles. the vesicles fuse with lysosomes containing proteases and the engulfed
material is processed for recycling. there are two pathways that can activate apoptosis, the first is the
death receptor or extrinsic pathway. it is triggered by activation of members of the tumor necrosis
factor receptor superfamily. the second means of initiating apoptosis is through the mitochondrial or
intrinsic pathway, this is set in motion by DNA damage. both pathways ultimately stimulate a set of
enzymes called caspases. the caspases interact with inhibitors of apoptosis proteins or I AP and the bcl-
2 family of proteins which individually have either Pro and anti a pop tonic properties. in some
malignant cells there is resistance to apoptosis due to overexpression of anti-apoptotic proteins, for
example survivin is an AI ap that is found in many cancers and predicts for poor outcomes and bcl-2 is
overexpressed in b-cell lymphomas as a result of the translocation of its gene. conversely deactivating
mutations of a pro-apoptotic molecule like Beck's is seen in some gastrointestinal tumors and leukemias.
anti-cancer agents have been developed targeting anti-apoptotic molecules, for instance short segments
of DNA complimentary to the RNA of bcl-2 or anti sense oligonucleotides have been designed to reduce
the translation of this anti apoptosis protein. activation of transcription factors can lead to a pop tonic
resistance, this occurs for example when members of the nuclear factor Kappa B or NF kappa-b family of
transcription factors are overexpressed in certain tumors which lead to increased transcription of anti-
apoptotic members of the ia P and bcl-2 families. the ubiquitin proteasome pathway regulates the
expression of transcription factors and other cell cycle proteins. certain molecules can suppress or
reduce NF kappa-b and ap one activation and inhibit tumor promotion bortezomib or Velcade is a
protozoa inhibitor that has shown promising results in multiple myeloma. it inhibits the protozoan which
leads to increased levels of the NF kappa-b inhibitor and therefore less anti-apoptotic proteins.