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Done by: Farhath JabienBatch: BBSD1_1012A
UOB: 09034657
Source:Science direct, 2002
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Lymphangiogenesis and functions of lymphaticvessels
It is formation of lymph vessels associated with tumor growth
from pre-existing ones.
Immunity
Transports white bloodcells and antigen-
presenting cells such asdendritic cells to andfrom the lymph
nodes
Homeostasis
Removal of interstitialfluid from tissues
Metabolism
Absorbs andtransports fattyacids and fats aschyle from
thedigestive system
http://en.wikipedia.org/wiki/White_blood_cellshttp://en.wikipedia.org/wiki/White_blood_cellshttp://en.wikipedia.org/wiki/Antigen-presenting_cellhttp://en.wikipedia.org/wiki/Antigen-presenting_cellhttp://en.wikipedia.org/wiki/Interstitial_fluidhttp://en.wikipedia.org/wiki/Interstitial_fluidhttp://en.wikipedia.org/wiki/Fatty_acidhttp://en.wikipedia.org/wiki/Fatty_acidhttp://en.wikipedia.org/wiki/Fathttp://en.wikipedia.org/wiki/Chylehttp://en.wikipedia.org/wiki/Chylehttp://en.wikipedia.org/wiki/Fathttp://en.wikipedia.org/wiki/Fatty_acidhttp://en.wikipedia.org/wiki/Fatty_acidhttp://en.wikipedia.org/wiki/Interstitial_fluidhttp://en.wikipedia.org/wiki/Interstitial_fluidhttp://en.wikipedia.org/wiki/Antigen-presenting_cellhttp://en.wikipedia.org/wiki/Antigen-presenting_cellhttp://en.wikipedia.org/wiki/Antigen-presenting_cellhttp://en.wikipedia.org/wiki/White_blood_cellshttp://en.wikipedia.org/wiki/White_blood_cells
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Lymphatic vessel formation implicated in
pathological conditions
Neoplasmmetastasis
Graft rejectionTissue
inflammatoryImpaired
wound healing
PsoriasisRheumatoid
Arthritis odema
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Lymphangiogenesis
Vascular endothelial growth factor (VEGF) C,D,Aspecific factors
identified Act predominatly via VEGF receptor 3, expressed
bylymphatic endothelial cells
VEGF-R3 activation promoteslymphatic endothelial cell
proliferation,migration,survival via extracelluar signal-regulated
kinase, PI3-k, C-Jun NH2-terminal kinase
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Source: Elsevier ,B.V. 2009
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Inhibition of lymphangiogenesis
Reduces the occurrence of lymphogenousmetastatic spreadThere are
various ways to inhibit :
Inhibiting VEGFR 3 pathwayUsing Cox-2 inhibitorUsing small
molecules kinase inhibitorsSequestering VEGF C & D
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THERAPEUTIC MANIPULATION OFLYMPHANGIOGENESIS
VEGF-C/ VEGF-D/VEGFR-3 signaling system wasstudied using animal
models and analysis of geneticlesions causing hereditary lymphedema
in humans
The outcome was lymphatic hyperplasia andlymphangiogenesis
during embryonic development inadult tissuesManipulation of this
pathway created the opportunity fortherapeutic strategies
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Inhibition of VEGFR-3 pathwayPotential inhibitors of the
VEGFR-3lymphangiogenic signaling pathway :
mAbs were synthesized to block the binding of VEGF-C and VEGF-D
to VEGFR-3One potential problem lymphatic vessel function in normal
tissues could be
compromised if VEGFR-3 signaling is required for
theintegrity/function of mature lymphatics.
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Source: cancer research, 2011
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Sequestering of VEGF-C and DThe binding of VEGF-C and D to
VEGFR-3 can be
prevented by a soluble version of the extracellulardomain of
receptor (tyrosine kinase catalytic domain)Using a transgenic mouse
model,
a soluble form of the ligand binding region (X) of theVEGFR-3
extracellular domain was expressed in theepidermis of the skin.X
consisted of the first three immunoglobulin homologydomains of
VEGFR-3 fused to the Fc-domain of the humanimmunoglobulin chainThe
outcome: Fetal lymphangiogenesis inhibition Development of a
lymphedema-like phenotype Blocked the growth of peritumoral
lymphatic vessels in a mouse
breast cancer model when delivered via an adenovirus
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Sequestering VEGF-C and VEGF-D
Source: adapted and modified: AmericanSociety of Clinical
Oncology, 2012
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Cox -2 inhibitorIt increases tumor cell apoptosis
lymphangiogenesis blocked along with growth andangiogenesis due
to inhibiton of VEGF pathway
Tested on mouse lung cancerExample: celecoxib
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Source: University ofLausanne,Switzerland
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Can lymphatic metastasis occur in theabsence of
lymphangiogenesis?
Several studies suggested that lymphatic endothelial cell
proliferation occurs in intratumoral and in peritumoral vessels
the pre-existing lymphatic vessels may equally contribute
tometastatic spread
It is possible tumors fail to induce lymphangiogenesis
andlymphatic metastasis occurs through the pre-existing vessels
E.g. Breast cancer
Lymphatic metastasis not only depend on generation of
newvessels, an increase in Lymphatic vessel denstiy
significantlyincreases a potential for a tumor cell to invade
lymphatic vesselsurface
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Problems with anti-lymphangiogenesis
Anti-lymphatics suitable for micrometastasisor in-transit
metastasis patientsIf tumors already induced lymphangiogenesis,
treatment not effectiveMultiple factors lead to
tumor-inducedlymphangiogenesis
Blocking 1 or 2 not enough to suppress
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Problems with anti lymphangiogenesis
Side effects:Inference with wound healing andtissue
regenerationLymphangiogenesis should be suppressed not onlyin lymph
node metastasis but in vital organs as well
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ReferencesDuong,T., et al.2011. Tumor lymphangiogenesis as
potential therapeutic target .
Journal of Oncology, 10(1), p 1-23Iwata,C., et al.inhibition of
Cyclooxygenase-2 suppresses lymph nodemetastasis via
Lymphangiogenesis. Cancer research,67(1),p 10181-10189
Nagahashi,M., et al. 2010. lymphangiogenesis: a new player in
cancer progression. World Journal of Gastroenterology, 16(32), p
4003-4012Sleeman,J.P.,2010. Understanding the mechanisms of
Lymphangiogenesis: ahope for cancer therapy? . Phlebolymphology,
17(2), p99-107Stacker,S.A., et al. ,2002. The role of tumor
lymphangiogenesis in metastatic
spread. The FASEB Journal, 16(1), p922-934Sundar,S.S., and
Ganesan,T.S., 2007. Role of lymphangiogenesis incancer. Journal of
Clinical Oncology, 25(27), p4298-4307Wissmann,C.,and Detmar,M.,
2006. pathways targetting tumor
Lymphangiogenesis. Clinical Research, 12, p6865-6868
