Stromal components in Breast, colon, stomach and pankreas, : 90% of non neoplastic cells in tumor mass

(1)

INTERAKSI HETEROTROPIK DAN BIOLOGI

ANGIOGENESIS

Stromal components in Breast, colon, stomach and pankreas, : 90% of non neoplastic cells in tumor mass

High grade invasive ductal carcinoma of the breast

Neoplastic cells are in continuous

communication with their non-neoplastic neighbors

Hodgkin’s disease: Lymphoma –

(2)

tumor development began

– Various signals from the cells  involve multiple distinct cell types  differentiation program  heterotypic signaling (signal from various type of cells)  to encourage or limit cell proliferation

CD34-antigen-positive fibroblast

CD117 antigen-

positive mast cells -smooth muscle actin- positive myofibroblasts

Stroma of squamous cell carcinomas of the oral cavity, pharynx, larynx

• Heterotyping signaling channels depend on :

– Mitogenic growth factors: HGF, TGF-, PDGF – Growth-inhibitory

signals: TGF-β – Trophic factors:

Insulin-like growth factor-1 & -2

• Heterotypic interaction play an

important role in driving many types of tumor promotion in during initial formation of

tumors.

(3)

Heterotypic interaction

•

during initial formation of tumors:

– play an important role in driving many types of tumor promotion

•

Tumor development:

– Carcinoma cells release PDGF  stromal cells have receptor for PDGF because of this inducer, stromal cells produce IGF-1  benefits for the growth & survival of cancer cells

– Stromal & epithelial cells collaborate in construction of ECM

– Endothelial cells –blood vessels & lymphatic ducts : vital component of normal & cancer tissue:

• Endothelial cells secrete growth factors that stimulate proliferation of nearby nonendothelial cells

Venule/arteriol Green:endothelial

Capilary vessels Green:endothelial

(4)

• Heterotypic interaction  maintain normal function continue to operate within

carcinomas, being required for the neoplastic cells to thrive and multiply within these

tumors.

Tumor ~ wounded tissue

Wound tissue PDFG & TGF-

Permeability blood vessels  Attract fibroblast + proliferation MMP + FGF

attract inflamatory cells

mitogenic factors stimulate endothelial cells

angiogenesis /neoangiogenesis

(5)

(6)

• In tumor :

– Release PDGF  attractant & mitogen for stromal cells

 stromalization

– Tumor-associated myofibroblasts from normal stromal fibroblast  desmoplastic stroma  hardness of tumor mass  deposition of extensive ECM collagen I, III, fibronectin, proteoglycans, gycosaminoglycans, uPA (urokinase plasminogen activator), MMP

– Carcinoma-associated fibroblasts (CAFs): mixed of fibroblasts and myofibroblasts

(7)

Stromal cells : active contributors to tumorigenesis

• Inaktivasi reseptor TGF-β-II pada sel fibroblas  aktivasi hiperproliferasi sel stroma  karsinoma pada sel epitel prostat  perlu sekali peranan fibrolas

Stromal cells : active contributors to tumorigenesis

• MEC + mammary stromal fibroblast (normal) tumor

txHMEC =

tumorigenic human mammary

epithelial cells

(8)

Figure 13.21 The Biology of Cancer (© Garland Science 2007)

• Myofibroblast ekspresi VEGF  bentuk

neovasculatura

(9)

Macrophages

• Macrophage :

– Monocyte chemotactic protein-1 

• macrophage chemoattractant protein 

• expressed by neuroectodermal and epithelial cancer cell types.

– VEGF, CSF-1, PDGF  recruit macrophage – CSF-1  monocyte  macrophage

differentiation

• Macrophages in tumor  play important roles in stimulating angiogenesis.

• Cancer cells/chemokine  attract more macrophages  secrete important angiogenic factors : VEGF & IL-8

• Hypoxic areas within tumors attract macrophages  VEGF secretion

• Macrophages + myofibroblast : secrete MMP

• MMP-9 

– Produced by Tumor –associated macrophages – involved in tumor progression 

• By enhancing angiogenesis

• By disrupting existing tissue structure

• By liberating critical mitogens that have been immobilized through tethering to proteoglycans of the ECM.

– MMP9  cleave IGFBP sequester IGF in the extracellular space.

• Two types of Macrophage :

– 1^st : Active collaborators in tumor progression, some cancer cells acquire the ability to inactivate or blunt the tumoricidal actions of the second type of macrophage

(10)

•

Tumor cells grew preferentially around blood vessels.

•

Tumor cells which were located

– more than 0.2 mm away from blood cells  nongrowing – Farther away  dying

•  0,2 mm  distance that oxygen can effectively

diffuse through living tissues

•

Tissue suffered from hypoxia  in danger of becoming necrotic

•

Vasculature  growth & survival of all types of tissue, normal & neoplastic

nekrotik nekrotik

hypoxia oxygenated

(11)

Mouse cornea:

wounding induces angiogenesis, chemotactic response to angiogenic factors

Angiogenesis:

Sprouting of cells from mature endothelial cells of the vessel wall

secretion of proteases, resolution of basal lamina, migration towards chemotactic gradient, proliferation,

VEGF is factor largely specific for endothelial cells,

bFGF can also induce,

tip cell stem

(12)

• Layout of vasculature 

– Is not regulated genetically

– Depend on the localized heterotypic interactions between the cells of the vasculature (incl.

endothelial, pericytes, smooth muscle cells) and nonvascular cells (incl. neoplastic cells and other types of the supporting stroma)

– Two ways of vasculature assembling:

• Myofibroblasts in tumor associated stroma  release chemotactic signals : SDF-1/CXCL12  recruit circulating endothelial precursors to the stroma

• Recruitment is also aided by VEGF

(13)

• Lymphatic vessels formation  is needed for regulators of fluid balance in the tumor stroma.

• Other factor for angiogenesis:

– TGFβ – bFGF – Interleukin-8 – Angiopoietin – Angiogenin – PDGF

• Capillaries in tumor :

– 3 x greater in diameter than normal

– Layout of blood vessels around and within tumor masses  quite chaotic – Plasma membranes of adjacent endothelial cells do not contact one another 

leave gaps  allow direct access of blood plasma to the cells surrounding the capillary  responsible for the deposition of fibrin in tumor parenchyma – Walls of capillaries : 10x more permeable than normal  due to the

deregulated production of VEGF within tumors

gap

Chaotic organization of tumor- associated vasculature

• Leakiness of tumor associated capillaries

 Accumulation of substantial amounts of fluid in the parenchymal spaces

within a tumor

– Normally  these fluid are drained by lymphatic vessels

• Solid tumor  cancer cells exerts

pressure on lymphatic vessels 

collapse of lymphatic vessels

(14)

• in rip-tag model of islet cell tumor progression, Angiogenic switch involves heterotypic interactions among 3 distinct

cell types:

– The release of

still-unidentified signals from the pre-malignant islet cells that recruit mast cells & quite possible macrophages

– The release of MMP-9 by inflammatory cells to activate latent VEGF – Proliferative response of

endothelial cells to activated VEGF

The Rip-Tag model of islet tumor cell progression

Transgene: SV40 large and small T transcription driven by insulin promoter Transcription in b-cells of islets of Langerhans

(15)

The angiogenic switch and recruitment of inflammatory cells

(16)

suppressed by physiologic

inhibitors

Stimulation of resting endothelial cells with angiogenic agents creates activated, growing endothelial cells, which soon express the Fas death receptor on their surface. Treatment of mature and recently formed endothelial cells with Tsp causes both groups of cells to secrete FasL. bind to FasR  apoptosis

(17)

(18)

Figure 1: Interaction between gastric cancer cells and stromal cells influences angiogenesis and lymphangiogenesis through various angiogenic factors and

cytokines. Yasuhiko Kitadai, J.Oncol. Volume 2010

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Stromal components in Breast, colon, stomach and pankreas, : 90% of non neoplastic cells in tumor mass

INTERAKSI HETEROTROPIK DAN BIOLOGI

ANGIOGENESIS