Fibroblast Growth Factors Fibroblast Growth Factors (FGFs)(FGFs)

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DefinitionDefinition

According to General Practice Notebook:According to General Practice Notebook:

Fibroblast Growth Factor is a peptide with Fibroblast Growth Factor is a peptide with cellular communication abilities e.g.cellular communication abilities e.g.

Stimulation of fibroblast and endothelial cell Stimulation of fibroblast and endothelial cell divisiondivision

Stimulation of angiogenesisStimulation of angiogenesis

FGFs Function in the CellFGFs Function in the CellFGF is a ligand that binds to Fibroblast Growth Factor FGF is a ligand that binds to Fibroblast Growth Factor Receptors (FGFR), which in turn through Receptors (FGFR), which in turn through tyrosine phosphorylation propagate signals through transduction pathway

Cell LinesCell Lines

FGFs induce mitogenic, chemotactic, and angiogenic FGFs induce mitogenic, chemotactic, and angiogenic activityactivityWhat effects does FGF have in the Mouse?What effects does FGF have in the Mouse?

Knock-Out MiceKnock-Out Mice

Dr. Miller et al, decided to knock-out:Dr. Miller et al, decided to knock-out:FGF-1FGF-1

FGF-2FGF-2

Double Knock-out of FGF-1 and FGF-2Double Knock-out of FGF-1 and FGF-2

There results were:There results were:

Mouse Knock-outs had no major Mouse Knock-outs had no major phenotypic variation from wild-typephenotypic variation from wild-type

Why these results?Why these results?

There are 22 known FGFsThere are 22 known FGFs

It is thought that the redundancy among It is thought that the redundancy among the 22 Fibroblast Growth Factors the 22 Fibroblast Growth Factors compensate for the knock-out of FGF-1 compensate for the knock-out of FGF-1 and FGF-2and FGF-2

Angiogenesis is:Angiogenesis is:

The formation of new capillary blood The formation of new capillary blood vessels from pre-existing onesvessels from pre-existing ones

– Requires migration, proliferation and differentiation of Requires migration, proliferation and differentiation of endothelial cells into blood vesselsendothelial cells into blood vessels

– Plays an important role in wound healingPlays an important role in wound healing

– Plays an important role in cancer as wellPlays an important role in cancer as well

Angiogenic Factors: FGF and Angiogenic Factors: FGF and VEGFVEGF

Tumor Cells release angiogenic Tumor Cells release angiogenic factorsfactors

Some scientist suggest that a tumor Some scientist suggest that a tumor requires blood supply in order to grow requires blood supply in order to grow beyond a few cubic millimetersbeyond a few cubic millimeters

A tumor cell releases FGF and VEGFA tumor cell releases FGF and VEGF

As a result of receptor activation, endothelial cells As a result of receptor activation, endothelial cells will secrete proteaseswill secrete proteases

The proteases digest basement membrane, which The proteases digest basement membrane, which migrate and proliferate to form new blood vesselsmigrate and proliferate to form new blood vessels

FGF-3 (int-2)FGF-3 (int-2)

Primarily expressed during developmentPrimarily expressed during development

First discovered in mouse mammary First discovered in mouse mammary carcinogenesis carcinogenesis

MMTV induces mammary tumors by acting as an MMTV induces mammary tumors by acting as an insertional mutagen, and activating transcription of insertional mutagen, and activating transcription of the nearby genes the nearby genes

FGF-3 (FGF-3 (intint) was found to be the site where the ) was found to be the site where the mouse mammary tumor virus (MMTV) usually mouse mammary tumor virus (MMTV) usually integratesintegrates

Mouse Mammary Tumor Virus Mouse Mammary Tumor Virus

Activates the promoter for FGF-3Activates the promoter for FGF-3This “turns on” FGF-3 at improper times during developmentThis “turns on” FGF-3 at improper times during development

MMTV and Human Breast CancerMMTV and Human Breast Cancer

Detectable MMTV Detectable MMTV envenv gene-related gene-related antigenic reactivity has been found in antigenic reactivity has been found in tissue sections of human breast cancertissue sections of human breast cancerThe human homologue of theThe human homologue of the int-2 int-2 locus locus has been found to be amplified and has been found to be amplified and expressed in 15% of the breast cancers expressed in 15% of the breast cancers There are still no clear proof that the There are still no clear proof that the human homologs to MMTV are related to human homologs to MMTV are related to human breast cancerhuman breast cancer

Breast CancerBreast Cancer

Dr. Granato et al., researched the effects Dr. Granato et al., researched the effects of FGFs in breast cancerof FGFs in breast cancer

They concluded that bFGF (basic fibroblast growth They concluded that bFGF (basic fibroblast growth factor) serum level is associated with the presence factor) serum level is associated with the presence of breast cancerof breast cancer

They proposed that bFGF as a noninvasive They proposed that bFGF as a noninvasive diagnostic tool for breast cancerdiagnostic tool for breast cancer

There are Elevated Levels of FGF There are Elevated Levels of FGF in Breast Cancer Patientsin Breast Cancer Patients