Factors affecting

tumor invasion
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Factors affecting tumor invasion

Supervisor
Dr. eman elhewady
Students :
• Mahmoud abd-elazeem
873
• Mahmoud emad-eldeen
875
• Mahmoud anter sheble
876
• Mahmoud mohamed arafa
879
• Mahmoud mohamed
mohamed 880
• Mahmoud mostafa fakhry
881
 Contents

Introduction:
• tumor (definition)
• Benign / malignant
• Malignant (invasion –metastases)
• Invasion (definition)

Factors affecting tumor invasion:

• Angiogenesis
• The lymphatic vasculature
• Cell motility
• Growth factor
• Integrins Expression
• EGFR (The epidermal growth factor receptor)
• MMPs ( matrix metalloproteinases)
• Tobacco
• Endostar
• MRI- CT

References.
 Introduction

Tumour definition:
An abnormal growth of tissue resulting from uncontrolled,
progressive multiplication of cells and serving no
physiological function.
There are two types of tumour:
Benign tumor
benign tumor is basically a tumor that doesn't come back
and doesn't spread to other parts of the body. A tumor is a
mass of tissue that serves no useful purpose and generally
exists at the expense of healthy tissues. Benign tumors
tend to grow more slowly than malignant tumors and are
less likely to cause health problems.
Malignant tumor(cancer)
malignant tumors grow faster than benign tumors and are
more likely to cause health problems. it can invade and
spreed to other parts of body by two procceses that called
invasion and metastasis.

Invasion:
Tumor invasion is a multistage process in which cellular
motility is associated with controlled proteolysis and that
involves interactions between tumor cells and the ECM.
During this process, malignantly transformed cells detach
from the primary tumor, migrate, and cross structural
barriers, including basement membranes and surrounding
stromal collagenous ECM. Degradation of stromal ECM is
also considered essential in tumor-induced angiogenesis.
Metastasis:
The process by which cancer spreads from the place at
which it first arose as a primary tumor to distant locations
in the body.
Basic components of the tumors :

All tumors, benign and malignant, have two basic

components:
(1) proliferating neoplastic cells that constitute their
parenchyma .
(2) supportive stroma made up of connective tissue and
blood vessels.

Although parenchymal cells represent the proliferating

"cutting edge" of neoplasms and so determine their
behavior and pathologic consequences, the growth and
evolution of neoplasms are critically dependent on their
stroma. The progression of a tumour from one of benign
and delimited growth to one that is invasive and metastatic
is the major cause of poor clinical outcome in cancer
patients.
Tumor invasion and metastasis formation are major
obstacles for successful cancer therapy. The invasion and
metastasis of tumours is a highly complex and multistep
process that requires a tumour cell to modulate its ability to
adhere, degrade the surrounding extracellular matrix,
migrate, proliferate at a secondary site and stimulate
angiogenesis. Knowledge of the process has greatly
increased and this has resulted in the identification of a
number of molecules that are fundamental to the process.
The involvement of these molecules has been shown to
relate not only to the survival and proliferation of the
tumour cell but, also to the processes of tumour cell
adhesion, migration, and the tumour cells ability to degrade
and escape the primary site as well as play a role in
angiogenesis.
These molecules may provide important therapeutic targets
that represent the ability to target specific steps in the
process of invasion and metastasis and provide additional
therapies.
Angiogenesis and lymphangiogenesis the development of
new blood vessels and lymphatics from the pre-existing
vasculature, respectively are processes with integral roles
in embryonic development and numerous diseases,
including cancer progression and metastasis and
inflammation.
Tumor cells near pre-existing blood vessels secrete growth
factors and chemokines such as VEGF-A ( vascular
endothelial growth factor A ), bFGF ( basic fibroblast growth
factor ), and TNFα ( tumour necrosis factor alpha ) that
stimulate quiescent vascular endothelium to enter the cell
cycle.
Angiogenesis is the better understood of the two processes,
in part due to the intense research focus placed upon the
field because of the significance of blood vascular
development for tumor growth and ischemic disease.

Factors affecting tumor invasion:

• Angiogenesis :
the process of new blood vessel formation from pre-existing
ones, plays a key role in various physiological and
pathological conditions, including embryonic development,
wound repair, inflammation, and tumor growth.
The nascent vascular bed expands by sprouting and
matures into a system of stable vessels. Hypoxia is an
important stimulus for expansion of the vascular bed.
Initially, cells are oxygenated by simple diffusion of oxygen,
but when tissues grow beyond the limit of oxygen diffusion,
hypoxia triggers vessel growth by signaling through
hypoxia-inducible transcription factors (HIFs
(HIFS))upregulate many angiogenic genes, include the gene
for Vascular Endothelial Growth Factor (VEGF-A).
VEGF-A can bind the receptors VEGFR-1 and VEGFR-2 to
induce endothelial cell migration, proliferation, and survival.
VEGF-A stimulates physiological and pathological
angiogenesis and is therefore currently being evaluated for
pro- and anti-angiogenic therapy. To induce angiogenesis,
many angiogenic growth factors, including basic fibroblast
growth factor (FGF-2)interact with signaling receptors
expressed on the endothelial cell (EC) surface that, with
some exceptions such as TNF and chemokine receptors, are
endowed with tyrosine kinase (TK) activity.
Additionally, many angiogenic growth factors are also
engaged in multiple interactions in the extracellular
environment and on the EC surface.
For instance, angiogenic growth factors bind a variety of
free or immobilized proteins, polysaccharides, and complex
lipids present in the extracellular environment that may
affect their integrity, stability, bioavailability, and diffusion.
Angiogenesis not only depends on the expression of
specific growth factors such as vascular endothelial growth
factor and fibroblast growth factor, but also on cell
adhesion to the extracellular matrix (ECM). During growth
of new blood vessels, adhesion to the ECM via integrins
regulates proliferation, survival, and motility of endothelial
cells.

• The lymphatic vasculature:

performs a crucial function by transporting fluid and

macromolecules, including fat, from tissues back to the
blood circulation. It also links tissue fluids to lymph nodes
as an immune surveillance system. A lack of molecular
markers specific to the lymphatic system has been an
impediment to lymphangiogenesis research until recently,
when the identification of several such markers, Lyve-
1( lymphatic veaael endothelial receptor 1), Prox-1, and
Podoplanin, has led to molecular insights into
lymphangiogenesis. Numerous pathologies are associated
with the lymphatics, such as the metastatic spread of
cancer, lymphangiomas, lymphangiectasias, and
lymphedema. Therapeutic strategies based upon the
expanding body of lymphatic knowledge are now being
considered.
Metastatic tumor cells can exploit the lymphatic
vasculature, as they frequently spread through the
lymphatic vessels and colonize lymph nodes. In particular,
breast cancer and melanoma are known to spread to lymph
nodes, necessitating radical surgery that destroys the
lymphatic vessel network and leads to impairment of
afferent lymphatic flow. Many patients who undergo radical
axillary lymph node dissection subsequently develop
lymphedema. Clinically, lymphedema presents as visible or
palpable tissue swelling. Breast cancer (BC)-related
lymphedema is a chronic condition that diminishes quality
of life and contributes to impairments in limb range of
motion, loss of strength, and functional limitations with
activities, such as lifting and reaching.
Growth factors capable of directly inducing the growth of
lymphatic vessels have been characterized. These factors,
VEGF-C and VEGF-D, are ligands for the endothelial cell-
specific tyrosine kinase receptors VEGFR-2 and VEGFR-3.8
VEGFR-2 is thought to be the principal mediator of
angiogenesis, whereas VEGFR-3 is crucial for development
and growth of lymphatic and blood vessels.
• Cell motility:
Cell motility is one of the defining characteristics of invasive
tumors, enabling tumors to migrate into adjacent tissues or
transmigrate limiting basement membranes and
extracellular matrices. Invasive tumor cells have been
demonstrated to present dysregulated cell motility in
response to extracellular signals from growth factors and
cytokines. Recent findings suggest that this growth factor
receptor-mediated motility is one of the most common
aberrations in tumor cells leading to invasiveness and
represents a cellular behavior distinct from-adhesion-
related haptokinetic and haptotactic migration. Cell motility
is mainly affected by growth factor-induced cell motility and
tumor cell invasiveness, and the implications for
development of targeted agents, with particular emphasis
on signaling from the epidermal growth factor (EGF) and
hepatocyte growth factor (HGF) receptors, as these have
most often been associated with tumor invasion. The
nascent models highlight the roles of various intracellular
signaling pathways including phospholipase C-gamma (PLC
gamma), phosphatidylinositol (PI)3'-kinase, mitogen-
activated protein (MAP) kinase, and actin cytoskeleton-
related events.
• Growth Factors:
Many cancer cells develop growth self-sufficiency by
acquiring the ability to synthesize the same growth factors
to which they are responsive. The protooncogene SIS,
which encodes the chain of platelet-derived growth factor
(PDGF), is overproduced in many tumors, especially low-
grade astrocytomas and osteosarcomas. Furthermore, it
appears that the same tumors also express receptors for
PDGF and are hence responsive to autocrine stimulation.
Although an autocrine loop is considered to be an important
element in the pathogenesis of several tumors, in most
instances the growth factor gene itself is not altered or
mutated. More commonly, products of other oncogenes
such as RAS (that lie along many signal transduction
pathways) cause overexpression of growth factor genes,
thus forcing the cells to secrete large amounts of growth
factors, such as transforming growth factor- (TGF-). This
growth factor is related to epidermal growth factor (EGF)
and induces proliferation by binding to the EGF receptor.
TGF-is often Subcellular localization and functions of major
classes of cancer-associated genes. The protooncogenes
are colored red, cancer suppressor genes blue, DNA repair
genes green, and genes that regulate apoptosis purple.
Integrins Expression:
Integrins are a family of heterodimeric transmembrane
glycoproteins mediating cell–cell and cell–ECM connections.
The integrin family consists of eight β and 18 α subunits
that assemble as heterodimers to form 24 distinct
integrins15.
The main ligands for integrins in the extracellular space are
extracellular matrix proteins, such as laminin and collagen,
as well as cellular counter-receptors. Integrins are linked to
the cytoskeleton through their cytoplasmic domains.
Integrins modulate the cytoskeleton via various
submembrane adaptor proteins and kinases.16 Integrins
transduce signals across the plasma membrane in both
directions; integrin binding to its ligands requires its
activation by inside-out signals. Conversely, integrin
ligation triggers outside-in signals that regulate different
aspects of cell behavior, including cell survival, control of
transcription, cell proliferation, cell motility, and
cytoskeletal organization.
Cell migration and invasion are crucial processes in a
variety of physiological and pathological conditions. They
have been identified as prerequisites for reproduction,
growth, and development. In addition, migration and
invasion perform critical functions not only in normal
homeostasis including proper wound healing and immune
system function but also in pathological conditions
including tumor progression via angiogenesis and
metastasis. These processes are controlled by a variety of
internal and external signals via complex signal
transduction cascades. A variety of molecules in focal
adhesions and the actin cytoskeleton are involved in cell
migration in a coordinated manner. For the process of cell
migration, the assembly and disassembly of cell adhesion
sites occur simultaneously at both the front and rear edge
of a cell. The invasion process requires the proteolytic
degradation of the ECM by several proteases, including
matrix metalloproteinases (MMPs), plasminogen activators,
and serine proteases.
Because integrins serve as transmembrane linkers between
their extracellular ligands and the cytoskeleton, they have
the capacity to influence cell migration during
embryogenesis, angiogenesis, wound healing, immune and
nonimmune defense mechanisms, hemostasis, and
oncogenic transformation.
Therapeutic Applications:
Preclinical studies have suggested that antagonists of
several integrins might be useful to suppress tumor
angiogenesis and growth, either alone or in combination
with current cancer therapeutics.
Of the several integrin antagonists undergoing clinical
evaluation for cancer treatment, all have proven nontoxic,
reduced angiogenesis and tumor growth in human
melanoma xenografts in nude mice and rats, most
carcinoma cells express integrin αvβ5, which has been
shown to promote tumor cell invasion. Targeting the alpha
v integrins may thus block both tumor cell invasion and
metastasis and tumor angiogenesis.
• EGFR (The epidermal growth factor
receptor):
autocrine pathway plays a crucial role in human cancer
since it contributes to a number of highly relevant
processes in tumor development and progression, including
cell proliferation, regulation of apoptotic cell death,
angiogenesis and metastatic spread. Tumor-induced
angiogenesis is well known as a key player in sustaining
local tumor growth, invasion and metastatic spread. In
cancer cells the EGFR autocrine pathway controls, in part,
the production of several proangiogenic growth factors,
including vascular endothelial growth factor (VEGF) and
basic fibroblast growth factor (bFGF). The link between
EGFR and VEGF signaling is also testified by the major
anticancer effect due to one of EGFR by selective anti-EGFR
agents of tumor-induced, VEGF-mediated angiogenesis . In
cancer cells, altered control of angiogenesis could be a
mechanism responsible for resistance to EGFR inhibitors in
vivo, as it has been shown in preclinical models with anti-
EGFR blocking MAbs (monoclonal antibodies). Among a
variety of approaches used to target EGFR signaling, EGFR
blocking monoclonal antibodies and small molecular weight
EGFR tyrosine kinase compounds have been successfully
developed. The results of a large body of preclinical studies
and clinical trials suggest that targeting the EGFR could
represent a significant contribution to cancer therapy. Both
types of agent exert a significant antiproliferative activity
when used alone or in combination with conventional
antitumor treatments, such as chemotherapy or radiation
therapy. Although the advanced clinical development of
EGFR blocking drugs demonstrates their efficacy in some
human metastatic diseases, such as lung, head and neck
and colorectal cancers, the issue of constitutive resistance
in a large number of patients and the development of
acquired resistance in the responders remains an
unexplored subject of investigation. Recent evidence
suggests the role of specific activating mutations within the
tyrosine kinase domain of EGFR to explain the dramatic
responses to small molecule tyrosine kinase inhibitors in a
subgroup of lung cancer patients. However, the intrinsic
molecular mechanisms of resistance to these drugs are still
unclear.
• MMPs ( matrix metalloproteinases)
belong to a family of structurally related proteolytic
enzymes that mediate degradation of the extracellular
matrix and the basement of membranes. High levels of
MMP activity have been linked to tumor growth, invasion,
and angiogenesis inflammation and may even work in a
nonproteolytic manner. The tissue inhibitor of
metalloproteinases family, including TIMP-1, 2, 3, and 4,
regulates the activity of multifunctional metalloproteinases.
Among TIMP members, TIMP-2 is most frequently
investigated because it is a unique member of the TIMP
family and involved in cancer progression and metastasis.
Recent studies have begun to unravel molecular pathways
linking inflammation and cancer. Inflammatory conditions
can initiate or promote oncogenic transformation and
genetic and epigenetic changes in malignant cells. An
inflammatory microenvironment further supports tumor
progression. Cancer-associated inflammation is marked by
the presence of specific inflammatory cells and
inflammatory mediators, including cytokines and
chemokines. Nuclear factor-κB (NF-κB) transcription factor
plays an essential role in innate and adaptive immune
responses, cell proliferation, apoptosis, and tumorigenesis.
Constitutive activation of NF-κB has been directly
implicated in tumorigenesis of various cancer types. Recent
evidence also suggests a crucial role for signal transducer
and activator of transcription (STAT) family in selectively
inducing and maintaining a procarcinogenic inflammatory
microenvironment, both at the initiation of malignant
transformation and during cancer progression. The
targeting of inflammatory mediators (chemokines and
cytokines, such as TNF-α and IL-1β), key transcription
factors involved in inflammation such as( NF-κB and STAT),
or inflammatory cells decreases the incidence and spread
of cancer. Therefore, anti-inflammation is an essential
strategy for the cancer therapy.

• Tobacco
Mounting evidence indicates that cigarette smoking not
only promotes tumorigenesis but also may increase the
spread of cancer cells in the body. However, the
intracellular mechanisms by which cigarette smoking
promotes metastasis of human lung cancer remains
enigmatic. Nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-
1-butanone (NNK) is an important component in cigarette
smoke and is formed by nitrosation of nicotine. mu- and
m-calpain (calpain I and calpain II) are major members of
the calpain family, which are ubiquitously expressed in both
small cell lung cancer and non-small cell lung cancer cells.
researches indicated that NNK (nicotine-derived
nitrosamine ketone) potently induces phosphorylation of
both mu- and m-calpain in association with their activation
and increased migration as well as invasion of lung cancer
cells. Treatment of cells by blocking phosphorylation of m-
and mu-calpain and resulted in suppression of NNK-induced
cell migration and invasion.
• Endostar
a novel recombinant human endostatin expressed and
purified in Escherichia coli with an additional nine-amino
acid sequence forming another his-tag structure, was
approved by the State Food and Drug Administration of
China (SFDA) in 2005 for the treatment of non-small-cell
lung cancer. However, the molecular mechanism of its
potent anticancer activity remains poorly understood and
warrants further investigations. In this study, we examined
the anti-invasive activities of endostar in vitro. The results
showed that endostar suppressed MDA-MB-435 cell
adhesion to the fibronectin-coated substrate in a
concentration-dependent manner. It could inhibit the wound
healing migration of MDA-MB-435 cells and invasion of
MDA-MB-435 cells through reconstituted ECM (matrigel).
Zymography revealed that endostar decreased the
secretion of MMP-2 and MMP-9. Endostar could also inhibit
the expressions of MMP-2 and MMP-9 in MDA-MB-435 cells.
Additionally, endostar exerted an inhibitory effect on the
phosphorylation of ERK1/2. Collectively, these data provided
a molecular basis for the anti-invasive effects of endostar.

• MRI- CT
The processes of tumor invasion and metastasis have been
well characterized at the molecular level, and numerous
biomarkers of tumor aggressiveness have been discovered.
Molecular imaging offers the opportunity to depict specific
cell markers relevant to tumor aggressiveness. Target-
specific molecular imaging probes for tumor invasiveness
have been developed for positron emission tomography
and optical imaging, but progress in MRI has been slower.
For example, proteases associated with tumor invasion,
such as specific matrix metalloproteinases or cathepsins,
can be targeted in vivo using optical and positron emission
tomography methods, but have not yet been successful
with MRI.
-Worldwide, cervical cancer is the second most common
malignancy in women, and is a major cause of morbidity
and mortality. Accurate tumor staging is essential for
optimal treatment planning and prognosis. Cervical cancer
is staged by clinical examination according to the
International Federation of Gynecology and Obstetrics
staging system. However, clinical staging has inherent
deficiencies in evaluating several parameters that are
critical for treatment planning. It is now widely accepted
that cross-sectional imaging, and in particular MRI, has an
important role to play in the staging of these tumors. MRI is
an excellent modality for depicting invasive cervical cancer:
it can provide objective measurement of tumor size and
provides a high negative predictive value for parametrial
invasion. MRI and positron emission tomography
(PET)/computed tomography (CT) play key roles in
identifying recurrent disease. Many studies have shown
that cancer cell differentiation and microvascular invasion
play a principle role in cancer progression and metastasis,
and non-invasive imaging techniques such as CT, MRI and
US assessing the differentiation and the surgical
resectibility and the prognosis of cancers are now of great
importance. This study aimed to explore the correlation of
triple-phase multi-slice CT scan with the histological
differentiation and intratumor microvascular/lymphatic
invasion of progressive gastric cancer.
• METHODS
A present study included 64 patients with gastric
cancer, all of whom underwent routinal and dual-phase
contrast enhancement multi-slice CT examinations of the
upper abdomen before surgery. The post-operative
specimens were used for determination of histological
differentiation, cancer cell invasion of intratumoral
microvascular/lymphatic vessel identified by CD34 and D2-
40 expression. Correlations between contrast
enhancement ratio (CER) of triple-phase multi-slice CT
scan in gastric cancer and histological differentiation as
well as intratumoral microvascular/lymphatic invasion
were compared and analyzed.
• CONCLUSIONS

CER of triple-phase multi-slice CT scan in gastric cancer is

closely correlated with intratumoral microvascular and
lymphatic invasion, and also could be used as a marker for
histological differentiation.
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