Origin of caf resident fibroblasts - PowerPoint Presentation

Slide1

Origin of

caf

resident fibroblasts

bone

marrow-derived progenitor cells

,

mesenchymal

stemcell

....

Marker for CAF

markers

for activated

CAF:

α-

SMA,

fibroblast

specific protein (FSP

)

platelet-derived

growth factor (PDGF) receptors-

β

fibroblast

activation protein (FAP

)

Vimentin

Name of markers

Functions

α-

smooth muscle actin (

α-

SMA)

Marker for

myofibroblasts

[

Fibroblast activation protein

 (FAP)

Marker for

myofibroblasts

Tenascin

-C

Regulates adhesion of cancer cells for

invasion

Periostin

Product of process of tissue

repair

Neuron glial antigen-2 (NG2)

More associated with pericytes. What fibroblasts come from

Vimentin

Plasma membrane associated

protein

Desmin

Marker for maturation of

microvessels

(to mark for

angiogenesis

Platelet derived growth factor receptor-α and β (PDGFR α and β)

Fibroblast specific protein-1 (FSP-1)- S100A4

Myofibroblasts

and fibroblasts make up

CAFs

FAP:

FAP is selectively expressed in CAFs and often used as a CAF marker

FAP

is originally identified as a membrane-bound serine protease implicated in extracellular matrix

remodeling.

FAP as a persistent activator of fibroblastic STAT3 through a

uPAR

-dependent FAK–

Src

–JAK2 signaling pathway

.

Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3–CCL2

Signaling.

STAT3–CCL2

signaling in this setting promoted tumor growth by enhancing recruitment of myeloid-derived suppressor cells (MDSC

).

fibroblastic

CCL2 expression is under STAT3 control and causally linked to the ability of FAP-expressing CAFs to promote tumor growth and immunosuppressive microenvironment.

Desmin

:

expressed

in fibrotic tissue in wound healing and in tumor '

desmoplastic

'

stroma

.

angiogenic

signals,

pericytes

are recruited to developing endothelial tubes and express

desmin

in increasing amounts as they mature and elongate to form a stable sheath around the newly formed

vessels.

Alpha SMA:

Alpha-smooth muscle actin (

α-

SMA)

 plays an important role in

fibrogenesis

.

Tenascin

:

as a member of

the extracellular matrix

plays

an important role in cancer cell proliferation and migration and tumor invasion in various types of cancer

Role of CAF

Tumor growth

Angiogenesis

Extra cellular matrix remodeling

Metastasis

Tumor invasion

chemoresistansis

Role of CAFs in cancer progression

ECM

remodelling

:

1-

collagen

: accumulation of type

I and III

collagens

Tumour

ECM stiffening

2-fibronectin:ligand for integrin receptor family including α5β1 receptor cell adhesion migration growth 3-hyaluronan:recruitment of tumour-associated macrophages

CAF

signalling

pathway

NFKB signaling

IL\stat3 signaling

TGFB\

smad

signaling

Foxo3a\VEGF\CCL2 signaling

And …

Secretion of soluble

factors :

HGF – EGF –

bFGF

– SDF1 – IL6 – IL8 – IL1B – IL10 – VEGFA –

TGFb

-PDGF

Cxcl2 - cxcl5 – cxcl8 – cxcl9 - cxcl10 – ccl7 – ccl20 – ccl26 – ccl2 – IDO – PGE2

HGF

:

activation

of the

c-Met pathway

in neighbouring cancer cells CAF-secreted HGF gives rise to an increased resistance of tumor cells to conventional tyroine kinase inhibitor against EGF receptorHGF secreted by CAFs enhanced the activation of uPA/uPAR

proteaseSDF1-IL8: cooperate in the

promotion of a complete angiogenic response in recruited

endothelial cells .CCL2: . CCL2 expression is associated with Th2 response.

CCL2-CCR2

signaling

recruit

myeloid cells such as TAMs to incite an

angiogenic

switch

and

myeloid-derived suppressor cells (MDSCs) to suppress and evade immune-mediated killing

Cxcl5:.

Downregulation

of CXCL5 could reduce cancer cell proliferation and migration through PI3K-AKT and ERK1/2 signaling

pathways.

Activation of the JAK/STAT pathway stimulates cell proliferation, differentiation, migration and apoptosis

.

STAT is also involved in vascular endothelial growth factor signaling and plays a pivotal role in

angiogenesis.

Cxcl8:

 acts as

a multifunctional

cytokine to modulate

tumor proliferation, invasion and migration in an autocrine or paracrine mannerCCL20: CCL20 activated Akt, ERK1/2 pathwayActivated stress-activated protein kinase/c-Jun kinase MAPKs,increased interleukin-8 expression result: increase of cell migration increase

of cell proliferation

CXCL2:

.

powerful

neutrophil

chemoattractant

cancer metastasis 

Angiogenesis

CXCL9\CXCL10:

.

CXCL9

, and CXCL10 can elicit antitumor

response accompanied with an enhanced infiltration of CD4+ and CD8+ lymphocytes.CXCL9/10/11, a regulator of PD-L1 expression in gastric cancer anti-angiogenic chemokines and they inhibit angiogenesis via the chemokine receptor CXCR3-B. These chemokines inhibit angiogenesis in colon carcinoma, melanoma and uterine cervical cancers .CCL7:. influence tumor migrationCCL7 activates the TGF-β pathway by enhancing Smad2 phosphorylation

CCL7 can enhance vascular permeability by recruiting TAMsCCL7 overexpression increases the recruitment of leukocytes and triggers type I T cell-dependent reactions

CAFs

secrete

several members of the MMP

direct degradation of

ECM, obviously associated with the generation of

space due

to

tumour

expansion, invasion or de novo

angiogenesis.

cleavage of membrane-bound growth factors or

cytokines as

well as their

receptors.cleavage of cell adhesion molecules like cadherins, leading to an increased motility and EMT.MMP-13 secreted by CAFs promotes tumour angiogenesis by releasing vascular endothelial growth factor (VEGF) from the ECM MMP-9, which in turn induces a clear EMT in prostate carcinoma cells, likely through E-cadherin negative regulation.