Fibroblast Growth Factors (FGFS) Increase Breast Tumor Growth Rate, Metastases, Blood Flow, and Oxygenation Without Significant Change in Vascular Density

Okunieff, Paul; Fenton, Bruce M.; Zhang, Lurong; Kern, Florian; Wu, Ting-Hsuan; Greg, J. Robert; Ding, Ivan

doi:10.1007/978-1-4615-0075-9_58

Cited by 26 publications

(15 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…More than 80% of prostate cancer cells express FGF8, and the levels of FGF8 expression correlate with the levels of invasiveness [5]. In breast cancer cells, cells that overexpress FGF1 or FGF4 grow faster than cells with low FGF expression in vivo [6]. The levels of FGFR expression also correlate with the invasiveness of cancer [7].…”

Section: Introductionmentioning

confidence: 99%

A Dominant-Negative FGF1 Mutant (the R50E Mutant) Suppresses Tumorigenesis and Angiogenesis

et al. 2013

View full text Add to dashboard Cite

Fibroblast growth factor-1 (FGF1) and FGF2 play a critical role in angiogenesis, a formation of new blood vessels from existing blood vessels. Integrins are critically involved in FGF signaling through crosstalk. We previously reported that FGF1 directly binds to integrin αvβ3 and induces FGF receptor-1 (FGFR1)-FGF1-integrin αvβ3 ternary complex. We previously generated an integrin binding defective FGF1 mutant (Arg-50 to Glu, R50E). R50E is defective in inducing ternary complex formation, cell proliferation, and cell migration, and suppresses FGF signaling induced by WT FGF1 (a dominant-negative effect) in vitro. These findings suggest that FGFR and αvβ3 crosstalk through direct integrin binding to FGF, and that R50E acts as an antagonist to FGFR. We studied if R50E suppresses tumorigenesis and angiogenesis. Here we describe that R50E suppressed tumor growth in vivo while WT FGF1 enhanced it using cancer cells that stably express WT FGF1 or R50E. Since R50E did not affect proliferation of cancer cells in vitro, we hypothesized that R50E suppressed tumorigenesis indirectly through suppressing angiogenesis. We thus studied the effect of R50E on angiogenesis in several angiogenesis models. We found that excess R50E suppressed FGF1-induced migration and tube formation of endothelial cells, FGF1-induced angiogenesis in matrigel plug assays, and the outgrowth of cells in aorta ring assays. Excess R50E suppressed FGF1-induced angiogenesis in chick embryo chorioallantoic membrane (CAM) assays. Interestingly, excess R50E suppressed FGF2-induced angiogenesis in CAM assays as well, suggesting that R50E may uniquely suppress signaling from other members of the FGF family. Taken together, our results suggest that R50E suppresses angiogenesis induced by FGF1 or FGF2, and thereby indirectly suppresses tumorigenesis, in addition to its possible direct effect on tumor cell proliferation in vivo. We propose that R50E has potential as an anti-cancer and anti-angiogenesis therapeutic agent (“FGF1 decoy”).

show abstract

Section: Introductionmentioning

confidence: 99%

A Dominant-Negative FGF1 Mutant (the R50E Mutant) Suppresses Tumorigenesis and Angiogenesis

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Breast tumors have higher expression of FGFR-1 than normal breast epithelium [87]. Overexpression of FGF-1 and FGF-4 in MCF-7 breast cancer cells increased tumor growth, blood flow rate, and lung metastases in vivo [88]. FGFs may also affect the invasive ability of breast cancer cells by stimulating secretion of matrix metalloproteinases.…”

Section: Bone Morphogenetic Proteins (Bmps) Fibroblast Growth Factormentioning

confidence: 99%

Molecular interactions between breast cancer cells and the bone microenvironment drive skeletal metastases

Siclari

Guise

Chirgwin

2006

Cancer Metastasis Rev

View full text Add to dashboard Cite

Breast cancer cells preferentially spread to bone. Bone metastases are currently incurable and therefore better treatments need to be developed. Metastasis is an inefficient, multi-step process. Specific aspects of both breast cancer cells and the bone microenvironment contribute to the development of bone metastases. Breast cancers express chemokine receptors, integrins, cadherins, and bone-resorbing and bone-forming factors that contribute to the successful and preferential spread of tumor to bone. Bone is rich in growth factors and cell types that make it a hospitable environment for breast cancer growth. Once breast cancer cells enter the bone, a highly complex vicious cycle develops, in which breast cancer cells secrete factors that act on bone cells and other cells within the bone (stem cells, T cells, platelets, adipocytes, fibroblasts, and endothelial cells), causing them to secrete factors that act on adjacent cancer cells. The steps in the metastatic cascade and the vicious cycle within bone offer unique targets for adjuvant treatments to treat and cure bone metastases.

show abstract

“…During embryogenesis, they regulate mesoderm induction, neurulation, and formation of the circulatory and skeletal systems (Fallon et al, 1994;Friesel and Maciag, 1999). During postnatal development, they play a crucial role in angiogenesis, tissue regeneration, inflammation, and pathogenesis of some tumors (Christofori and Luef, 1997;Friesel and Maciag, 1999;Woolley et al, 2000;Javerzat et al, 2002;Okunieff et al, 2003). The biological effects of FGFs are mediated through the activation of four transmembrane phosphotyrosine kinase receptors (FGFR1-4) (McKeehan et al, 1998), with the participation of cell surface proteoglycans (Ornitz and Itoh, 2001), and consequently require FGF release.…”

mentioning

confidence: 99%

Novel Cross-Talk between Three Cardiovascular Regulators: Thrombin Cleavage Fragment of Jagged1 Induces Fibroblast Growth Factor 1 Expression and Release

Duarte

Kolev

Kacer

et al. 2008

MBoC

View full text Add to dashboard Cite

Angiogenesis is controlled by several regulatory mechanisms, including the Notch and fibroblast growth factor (FGF) signaling pathways. FGF1, a prototype member of FGF family, lacks a signal peptide and is released through an endoplasmic reticulum-Golgi-independent mechanism. A soluble extracellular domain of the Notch ligand Jagged1 (sJ1) inhibits Notch signaling and induces FGF1 release. Thrombin, a key protease of the blood coagulation cascade and a potent inducer of angiogenesis, stimulates rapid FGF1 release through a mechanism dependent on the major thrombin receptor protease-activated receptor (PAR) 1. This study demonstrates that thrombin cleaves Jagged1 in its extracellular domain. The sJ1 form produced as a result of thrombin cleavage inhibits Notch-mediated CBF1/Suppressor of Hairless [(Su(H)]/Lag-1-dependent transcription and induces FGF1 expression and release. The overexpression of Jagged1 in PAR1 null cells results in a rapid thrombin-induced export of FGF1. These data demonstrate the existence of novel cross-talk between thrombin, FGF, and Notch signaling pathways, which play important roles in vascular formation and remodeling. INTRODUCTIONFibroblast growth factor (FGF) family members exhibit a variety of biological activities. During embryogenesis, they regulate mesoderm induction, neurulation, and formation of the circulatory and skeletal systems (Fallon et al., 1994;Friesel and Maciag, 1999). During postnatal development, they play a crucial role in angiogenesis, tissue regeneration, inflammation, and pathogenesis of some tumors (Christofori and Luef, 1997;Friesel and Maciag, 1999;Woolley et al., 2000;Javerzat et al., 2002;Okunieff et al., 2003). The biological effects of FGFs are mediated through the activation of four transmembrane phosphotyrosine kinase receptors (FGFR1-4) (McKeehan et al., 1998), with the participation of cell surface proteoglycans (Ornitz and Itoh, 2001), and consequently require FGF release. FGF1 is a potent proangiogenic factor, which supports the survival of endothelial cells in vitro, stimulates the growth of vessels, and enhances the repair of infarctic lesions in vivo (Sellke et al., 1996;Schumacher et al., 1998;Friesel and Maciag, 1999;Buehler et al., 2002). FGF1 lacks a signal peptide in its primary structure (Friesel and Maciag, 1999), and, similar to other signal peptide-less extracellular regulatory proteins, it undergoes nonclassical export (for review, see Prudovsky et al., 2003;Nickel, 2005;Prudovsky et al., 2008).Thrombin, the key protease of the blood coagulation cascade, induces the expression of several growth factors (Bassus et al., 2001;Cucina et al., 2002;Cao et al., 2006) and exhibits proangiogenic activity (Steinhoff et al., 2005). We recently demonstrated that thrombin, through activation of the protease-activated receptor (PAR) 1, rapidly induces FGF1 expression and its release under nonstress conditions, revealing an interplay between thrombin signaling and nonclassical FGF1 release (Duarte et al., 2006). PAR1 is activated through the proteolyti...

show abstract

Fibroblast Growth Factors (FGFS) Increase Breast Tumor Growth Rate, Metastases, Blood Flow, and Oxygenation Without Significant Change in Vascular Density

Cited by 26 publications

References 6 publications

A Dominant-Negative FGF1 Mutant (the R50E Mutant) Suppresses Tumorigenesis and Angiogenesis

A Dominant-Negative FGF1 Mutant (the R50E Mutant) Suppresses Tumorigenesis and Angiogenesis

Molecular interactions between breast cancer cells and the bone microenvironment drive skeletal metastases

Novel Cross-Talk between Three Cardiovascular Regulators: Thrombin Cleavage Fragment of Jagged1 Induces Fibroblast Growth Factor 1 Expression and Release

Contact Info

Product

Resources

About