Cellular and Molecular Biology of Cancer: Role of Hypoxia in Angiogenesis Regulation and Molecular Events in Metastatic Cascade

This essay discusses the role of hypoxia in the regulation of angiogenesis in cancer, key factors involved in the process of regulation of angiogenesis, and molecular events involved in the metastatic cascade. It also describes different ways to treat cancer cells through the assistance of molecular events included in the metastatic cascade.

Cellular and Molecular
Biology of Cancer

Contents
ESSAY-1..........................................................................................................................................1
INTRODUCTION...........................................................................................................................1
MAIN BODY...................................................................................................................................1
CONCLUSION ...............................................................................................................................5
ESSAY-2..........................................................................................................................................6
INTRODUCTION...........................................................................................................................6
MAIN BODY...................................................................................................................................6
CONCLUSION..............................................................................................................................11
REFERENCES FOR ESSAY 1.....................................................................................................12
REFERENCES FOR ESSAY 2.....................................................................................................12

ESSAY-1
INTRODUCTION
Cancer is known as fatal diseases in the world , it cause more the twenty five percent of
death in united kingdom. These number are increasing continuously due to prolonged life
expectancy, population growth and more number of risk factors as like lack of activity, more
number of obesity, and smoking (Murugan, 2019). A general characteristic of most tumours is a
very few level of oxygen, is known as hypoxia, the seriousness of which depends upon the kinds
of tumour. In expanding tumour or intensively proliferating tissue, demand of oxygen is more
than the supply of oxygen, the existing vasculature and the distance between the cells are also
increases. Therefore, it creates obstruction in the diffusion of oxygen and making even more
hypoxic condition. In the hypoxic tumour cells poorer oxygen condition than the normal cells
which is generally 1-2% O2 and below (Du, and et. al., 2021). Oxygen level of tumour is
depends upon the stage, size, method of oxygen measurement, initial oxygenation of the cells
and the measurement which was performed. This essay will going to discuss about the role of
hypoxia in the regulation of angiogenesis in cancer. This essay will also include the key factors
in the process of regulation of angiogenesis because of hypoxia in cancer cell. Finally this essay
will argue about those pathway which is involved in the process of regulation of angiogenesis
due to hypoxia in cancerous cell (Ma, and et. al., 2020).
MAIN BODY
Generally, hypoxia is a condition in cancerous cell, in which oxygen supply to cancerous
cell is less than the demand of oxygen. Cancerous cells commonly respond in various way
towards lowering oxygen level leading to cell survival or cell death, it is partially depends on the
exposure time to hypoxia. Acute hypoxia is short term hypoxia and it occurs when occlusion of
blood vessel lasts for several minutes at least. In acute hypoxia, cells have been allowed to
survive in adverse situation through activating autophagy, which is an metabolic and apoptotic
adaptation of cells (Mortezaee, 2020). It is gained by lowering the oxidative metabolism. In the
other hand cycling hypoxia led to enhanced ROS (reactive oxygen species) generation, which
contribute to progression and survival of tumour cell. Both long term and short term hypoxia are
associated to increase radio-resistance of cancerous cell. Acute hypoxia is related with more
aggressive phenotype of tumour (Joseph, and et. al., 2018). In the earlier stage of malignant
1

progression, a tumour is placed in the inactive stage in a non vascular space at which the pace of
cell differentiation is balance by the cell apoptosis. Later the tumour cells undergoes a changes to
form a non angiogenic stage to active stage and this process is happened through so called
angiogenic switch (Chang, and et. al., 2020). For the progression of tumour cells, angiogenesis is
important because growth of the tumour cells often outstrips the supply of nutrients and oxygen.
Angiogenesis play a vital role in both the formation and progression of tumour. Tumour vessels
are more leaky, poorly functioning and highly irregular, despite active angiogenesis. Even in
more vascular tissue, this leads to HIF- a stabilisation and hypoxic domains, even in more
vascular tissue (Zhu, and Zhang, 2018). HIF activation and hypoxia have intense effects on the
the biology of tumour, because the expression of HIF-1Aa or HIF-2a are associated metastatic
illness and less prognosis in number of cancers, involving colon, liver, neck and head, skin,
brain, pancreas and breast. This is due to partially therapeutic resistance because it is stubborn to
treat the hypoxic tumour through the radiation therapy as molecular oxygen is needed for the
cytotoxic effects of radiation therapy (Kochan-Jamrozy, and et. al., 2019). Due to the HIF
mediated expression of ATP- dependent efflux pump of drug and poor delivery of drug,
chemotherapy is also not effective in hypoxic tumours. HIF pathway and Hypoxia activation in
cancerous tissues are an vital stimulus for growth of blood vessels. HIF-1a ans HIF-2a control
the expression of a suite of genes of pro-angiogenic, which including Ang-1, Ang-2 , Vegf and
Tie-2, numbers of which themselves are worked as a biomarker to tumour hypoxia. Ang-1 boost
tumour angiogenesis through engaging pericytes for thee maturing vessels. Extra expressed in
glioma, breast cancer and stem cell factor is a HIF-1 alpha transcriptional target which arbitrate
neovascularization by increasing EC migration and survival and mobilization of EPC (Klaunig,
2018). As well as the well defined pro-angiogenic genes controlled by the HIF. According to the
recent study additional effector molecules can regulated by hypoxia, which maximise the
regulatory capacity of HIF (Sahebi, and et. al., 2020). In the growth of angiogenesis in growth of
cancer some growth factors are involved which are following such as; acidic & basic fibroblast
growth factor, vascular endothelial growth factor family, angiostatin, angiogenin, transforming
growth factor, tumour necrosis factor-alpha, and so on. Plated- delivered endothelial growth
factor, hepatocyte growth factor, epidermal growth factor, placental growth factor and
granulocyte colony stimulating factors are also play a vital role in regulation of angiogenesis in
cancer cells. Some factors are work as an inhibitors for tumour cells like cytokines, proteases
2

and protease inhibitors (Kim, and et. al., 2018). There are various protein which occur naturally
and can inhibits the angeogenesis, involving endostatin, interferon, platelet factor 4, angiostatin,
prolactin 16kd fragment, thorombospondin, and metalloproteinase-1, -2, & -3 tissue inhibitors.
By one or more fragments of plasminogen together form Angiostatin. It promote apoptosis in
tumour cells and endothelial cells, and stops formation and the migration of tubules in
endothelial cells.
Angitensin treated tumours' immunohistochemical examination point out a lowering in the
expression of mRNA for bFGF and VEGF (Devarajan, Manjunathan, and Ganesan, 2021).
Enostatin, it is a twenty kilodalton C-terminal fragment of collagen of type XVII, it is a part of
3
Illustration 1: steps of hypoxia and role of G6P1
Sources: https://www.researchgate.net/figure/Schematic-model-for-the-role-
G6PI-plays-in-regulation-of-hypoxia-induced-angiogenesis-
in_fig6_312178910

the basement membrane. It induce the migration and proliferation of endothelial cells and also
inhibits the growth factors like bFGF and VEGF-A. Since there are two types of factors which
affects the angiogenesis growth that one is angiogenesis promoter and another one is
angiogenesis inhibitors. When the balance between these two factor are disturb in the body then
either it provokes or inhibits the process of angiogenesis in tumour cells (Luo, and Wang, 2019).
When promoter increased then enhances the growth of tumour cells but on increasing the
number of inhibitors, it inhibits the growth of tumour cells. VEGF-A, that is a Vascular
endothelial growth factor A is a main regulator of angiogenesis in disease condition and under
normal both. It belongs to a gene factors' family which also surrounds VEGF-B, VEGF-C,
VEGF-D, VEGF-E and PIGF ( placenta growth factor). All of these factors have various level of
specificity and different affinities for VEGFR that is tyro-kinase receptors -1,-2,&-3. when the
binding of VEGF-A with VEGFR-2 then it leads angiogenesis (Zhu, and Zhang, 2018). In
addition, VEGF-C and VEGF-D prefer to bind with VEGFR-3, which expressed more
dominantly on lymphatic EC, that results in the differentiation of lymphatic vessels (Sahebi, and
et. al., 2020). VEGF play a role in exceeding the angiogenesis in cancer by a complex paracrine
and autocrine signalling pathway. VEGF show a vital role in promoting the functions of stem
cell of cancer and also in the initiation of tumour. In hypoxic tumour, TAMs (tumour associated
macrophages) secrete VGEF and known for its protumour functions (Minassian, and et. al.,
2019). In the tumour micro environment, VEGF interacts with essential immune cells which is
regulatory T cells and CD4+ forkhead box protein p3 that is FOXP3, it is a very good suppressor
of immunity for anticancer. In TME, more number of fibroblasts are present and known for
support growth of tumour, also release VEGF (Schito, 2019).
4

CONCLUSION
According to the above discussion it has been concluded that hypoxia is a
condition where demand of the oxygen is more then the supply of oxygen. Exposure time of
cancerous cell to hypoxia play a vital role in terms of deciding the fate of that cells that is leading
to death of cells or survival of cells. Hypoxia lead to generation of reactive oxygen species cells
which decide the survival and death of cancerous cells. In this essay, It has been seen that in
terms of cancerous cell progression hypoxia played a very crucial role. When the balance
between cancerous cell promoter and cancerous cell inhibitor disturb in the human body then it
can cause angiogenesis in cancer on increasing the number of cancerous cell. But when the
number of inhibitor increases then it suppress the activity of cancerous cell. VEGF is a type of
promoter of cancerous cell where and interferon and many more like this are inhibitors for
5
Illustration 2: steps involves in hypoxia induce angiogenesis in cancer
Source: https://www.researchgate.net/figure/STAT3-in-hypoxia-induced-angiogenesis-
Hypoxia-activates-STAT3-in-both-tumor-cells-and_fig4_318914913

cancerous cell growth. In this essay the role of hypoxia in the progression of angiogenesis in
cancer has been discussed with the key factor involved in the regulation of angiogenesis in
cancer. Different pathways responsible for angiogenesis in cancer has also been discussed in this
essay.
ESSAY-2
INTRODUCTION
Metastasis, it is one of the major reasons of death worldwide. At the time of development
of tumour, cancer cells come into genetic mutations, adopt their micro-environment and promote
angiogenic germination which can effectively lead to metastasis. Solid tumour's metastatic
progression can be split into 5 main steps, which are: (1) Invasion of the cell migration and
basement membrane, (2) Intravasation into the neighbouring lymphatic or vasculature system,
(3) Staying alive in the lymphatic or vasculature circulation, (4) Discharge from vascular system
to secondary tissue and in last (5) formation of colony at the site of secondary tumour (Yu, and
et. al., 2019). Every stages of metastasis forces various, frequently worst conditions potentially
taxing challenging to the cancerous cell to complete (Cortés-Hernández, Eslami-S, and Alix-
Panabières, 2020). The number of live cancerous cell which survive and well complete all stage
lowering precipitously, as the cascade progresses. In this essay several molecular event involved
at various steps in the metastatic cascade will be include. Different way to treat the cancer cell
through the assist of the molecular events includes in the metastatic cascade will going to
describe in this essay.
MAIN BODY
The metastatic cascade explains as the procedure by which aggressive cancerous cell
leave the primary tumour, by travelling via the bloodstream, and at the end reach the distant body
parts to evolve one or more metastases. There are several steps include in the metastasis of
cancer. These steps involves separation from the primary tumour, invasion via basements
membranes or neighbouring tissues, entry and live in the vascular circulation, peritoneal space
or lymphatics and arrest in the distant end target body parts (Berish, and et. al., 2018). Step of
metastatic cascade and molecular events involved for cancer treatments are following: Step 1:
invasion and migration: Metastasis is started at the time of invasion and migration where
cancer cells puncture the basement membrane and cross as single cells or through collective that
6

is via stromal micro-environment. Invasion by the basement membrane is known as
differentiating steps to separate precancerous neoplasia & malignant tumour in which enhance
fibre thickness, linearized fibre architecture and collagen deposition hand out to a stiffer
condition (Lu, and et. al., 2019). By the cycle of contraction and protrusion cell mechanically
remodel ECM, and by using metalloproteinases cells chemically deteriorate the matrix as they
migrate. Apart from this, matrix stiffness and cancer cell contractility made a positive feedback
loop resulting downstream impacts on behaviour of cell at the time of progression of metastatic.
Through the use of organoids partially reduce these restriction through more better representing
phenotypic and genotypic diversity in structure. Organoids seizes number of genomics variations
present in the solid tumours and act as preclinical drug screening cancer model, shown to
establish a relationship with clinical response to common therapeutics of cancer. In additionally,
spheroids are the groups of cells which used to study invasion and migration (Garner, and de
Visser, 2020). Stability and reproducibility make these appropriate to identifying characteristic
of the cancer micro-environment which derive metastatic behaviour of cell.
7
Illustr
ation 3: Metastatic cascade
Source: https://www.google.com/search?
q=metastatic+cascade+in+cancer&tbm=isch&ved=2ahUKEwjYvoS4lYf5A
hWfi9gFHSehCegQ2-
cCegQIABAA&oq=metastatic+cascade+in+cancer&gs

Induction of hypoxia in a spheroid model was seen to be necessary in obtaining the tumour stem
like cell phenotype, a main target in present therapeutics of cancer (Zhang, and et. al., 2019).
Through modelling the relationship in between the cancer micro-environment and the cell
behaviour, number of therapeutics can be evolved. Spheroid model can also give a platform to
study the differentiating elements between collective and single cell migration. Myoepithelial
cells neighbouring the basement membrane are thought to keeps a suppressor of tumour role
which can be lost at the time of neoplasia. Tumour cells can put in directly into collagen bed to
evaluate the direction, morphology and cell speed at the time of migration. Significantly there is
now important evidence to put forward that collagen matrix alignment is a autograph of
metastatic cancer and can be utilise to forecast result of patient (Berish, and et. al., 2018). Step 2:
Angiogenesis and intravasation: Angiogenesis of tumour touch on the origination of
vasculature at the time of progression of tumour, allowing delivery of oxygen and nutrients and
as well as excretion of the waste product. Due to absent of basement membrane and perivascular
coverage, newly formed cancer vasculature is more permeable and less mature resulting leakage
of proteins present in plasma which is further clear the way intravasation of tumour cell and
formation of new vessel. Angiogenesis promote metastasis through empowering transport of
cancer cells to distant site through lymph and vascular systems. As like perfusable models which
empower the production of endothelial networks application in the recognition of the specific
influences of angiogenesis on the progression of cancer. In lab assays of angiogenesis
concentrate first and foremost on cell migration, endothelial barrier integrity, cell proliferation
and vessel formation (Li, and et. al., 2019). In the recent time more advanced models have been
evolved to learn barrier function and patient specific formation of endothelial tubule by
endothelial embedding cells, within three dimensional hydrogels, including sample of patient
derived. Because of interstitial pressure and blood flow promote cancer angiogenesis, number of
micro-fluidic systems concentrates on recapitulating this in vitro (Riggi, Aguet, and
Stamenkovic, 2018). In addition very large number of inter-tumour heterogeneity in the activity
of angiogenic depends partially on those organ from where it arose and subtype of cancer, due to
difference of organ specific in the anti and pro angiogenic molecule secretion outline of stromal
cell populations. Therefore, the development of very unique individualized experimental system
will empower characterization of angiogenic habits in various kinds of cancer for single
8

patients, leading to enhancements in the models of drug screening. Micro-fluidic system gives
permission to the amalgamation of fluid flow and are compliant to current time imaging
capability (Nishida, and et. al., 2020). Step3: live in the circulation and attachment to the
endothelium: However, some number of cancerous cells reaches in the body fluid circulation,
even very less number of these are survive the immune stress, red blood cell collisions and
haemodynamic shear forces they come up against once there. CTC (circulating tumour cells) are
arrest in a circulatory vessels and extravasate by two primary mechanisms: adhesion after rolling
and physical occlusion. At the time of physical occlusion, a circulating tumour cells' diameter
exceed that of the micro vasculature, and the cell became lodge at the time before extravasating
and attaching (Dongre, and Weinberg, 2019). At the time of rolling- adhesion, circulatory
tumour cells collide to the endothelium, roll through P-selectin or E- selectin binding, and arrest
through vascular cell adhesion molecule-1 (VCAM-1) or by intercellular adhesion molecule-1
( ICAM-1) binding (Steinbichler, and et. al., 2020). Micro tubing and micro fluidic systems
enabling the gathering of both clustered and single circulatory tumour cells from the blood of
patient have contributed effectively to understanding the metastasis of cancer. These stage
frequently take on surfaces functionalized with the circulatory tumour cells specific adhesion
antibodies and proteins to improve adhesion dynamics for circulatory tumour cells at the time of
reducing that of leukocytes also associated in the whole blood (Li, and et. al., 2020). Some of the
physical entrapment in the flow may also be use to separate the clusters of circulatory tumour
cells which have been suggested to have enhanced metastatic capability as compare to single
circulatory tumour cells. A three dimensional printing of carbohydrate glass sacrificial fibre may
make more perfusable, controlled and controlled vascular networks . Live cell lithography
technique was evolved for better control of tumour cells. By the correlation of clinical data,
theranostic stages with circulatory tumour cells seperated from patient blood have the capability
to enhance the clinical results. (4) Extravasation and colonization: Go along with arrest in the
circulatory vessel, tumour cells must extravasate to the colonize new site from the circulatory
vessel (Wee, and et. al., 2019). This process not similar to the intravasation, in which tumour
cells navigate tumour modified stroma through durotactic and chemotactic gradients in the
direction of leaky, nascent vasculature with not feeling haemodynamic stressors rather the
vasculature during extravasation which is broke by cancer cells actively experience shear force
of fluids because of blood flow and cancer cells is healthier (Murugan, 2019). Metastatic niches
9

keeps ECM and cell types compatible for cancer cells growth and survival involving space
around blood capillaries and perivascular niches at where tumour cells can grow or seed.
Mineralised hydroxyapatite incorporated extra cellular metastasis, ex vivo bone scaffolds and
osteo-differentiated mesenchymal totipotent cells have all been represented to recognise
appropriate cell behaviour of tumour cells. To observe interaction among the non-parenchymal
cells, hepatic cells and cancer cells commercially use micro fluidic model as liverChip model.
Presently, metastatic colonisation methods are used to concentrate on earlier stages of tumour.
Because colonisation is that stage at where tumours achieve its lethality and no drug therapy
work (Wagner, and Koyasu, 2019).
10
Illustration 4: The metastatic cascade
Sources: https://www.google.com/search?
q=metastatic+cascade+in+cancer&tbm=isch&ved=2ahUKEwjYvoS4lYf5A
hWfi9gFHSehCegQ2-
cCegQIABAA&oq=metastatic+cascade+in+cancer&gs

CONCLUSION
According to the above discussion it has been concluded that the procedure by which
aggressive cancerous cell leave the primary tumour, by travelling via the bloodstream, and at the
end reach the distant body parts to evolve one or more metastases. There are four steps involve in
metastasis cascade which has been explained in this essay. In this essay, it has also been included
that how the molecular events involved in various stages in the metastasis cascade play a
significant role in the exploitation of treatment of cancer.
11

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