Transcript The VEGF ligand

The Role of VEGF in Breast Cancer
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Angiogenesis and the
VEGF ligand in cancer
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Overview
Angiogenesis (the formation of new blood vessels from existing ones) is an
important process in the growth of malignant tumors1,2
An association between VEGF and angiogenesis, malignancy, and
metastasis has been established1,2
Many pro- and anti-angiogenic cellular factors regulate angiogenesis1,2
Research thus far suggests that VEGF is a potent and predominant factor
in this process1,2
.
References: 1. Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23:1011-1027. 2. Ferrara N. Endocr Rev. 2004;25:581-611.
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Several critical mechanisms are involved in tumor growth
Reprinted from Hanahan D, Weinberg RA, “The Hallmarks of Cancer,” in Cell,
2000;100:57-70, with permission from Elsevier.
Angiogenesis is 1 of the 6 acquired cellular capabilities leading to
malignant growth1
Reference: 1. Hanahan D, Weinberg RA. Cell. 2000;100:57-70.
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VEGF is a potent and predominant factor in the angiogenic
process
Many pro- and anti-angiogenic cellular factors regulate angiogenesis
Growth factors involved in tumor angiogenesis include
— Vascular endothelial growth factor (VEGF)
— Basic fibroblast growth factor (bFGF)
— Endostatin
— Platelet-derived growth factor (PDGF)
Endothelial cell survival in newly formed vessels is VEGF-dependent
The VEGF ligand is the most potent direct-acting angiogenic protein known
— VEGF is relatively unique among growth factors due to its specificity for the
vascular endothelium
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The VEGF ligand: at the center of the angiogenic pathway
The VEGF ligand:
• Stimulates vascular endothelial cell growth, survival, and proliferation1,2
• A genetically stable protein2-5
• Continuously expressed throughout the entire tumor life cycle6
• Direct and continuous VEGF inhibition is an important antitumor strategy
References: 1. Ferrara N. Endocr Rev. 2004;25:581-611. 2. Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23:1011-1027. 3. Bergers G, Benjamin LE.
Nat Rev Cancer. 2003;3:401-410. 4. O’Dwyer PJ. Oncologist. 2006;11:992-998. 5. Mukhopadhyay D, Datta K. Semin Cancer Biol. 2004;14:123130. 6. Folkman J. In: Devita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. Vol 2. 7th ed. Philadelphia, PA:
Lippincott Williams & Wiklins; 2005:2865-2882.
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The VEGF ligand in breast cancer
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VEGF ligand expression is an
important factor in breast cancer
“Angiogenesis, the process of new blood vessel formation,
plays a central role in both local tumor growth and distant
metastasis in breast cancer.”
— Schneider and Miller. J Clin Oncol, 2005.1
“[VEGF], a potent angiogenic factor, has been reported
to be associated with a poor prognosis in primary
breast cancer.…”
— Foekens et al. Cancer Res, 2001.2
References: 1. Schneider BP, Miller KD. J Clin Oncol. 2005;23:1782-1790. 2. Foekens JA, Peters HA, Grebenchtchikov N, et al. Cancer Res.
2001;61:5407-5414.
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The VEGF ligand is a key mediator
of breast tumor angiogenesis
Reprinted with permission from the American Association for Cancer Research.
Relf M, LeJeune S, Scott PA, et al. Cancer Res. 1997;57:963-969.
Relf et al: VEGF is one of the most important mediators of tumor
angiogenesis in breast cancer1
— Of known pro-angiogenic factors measured, only VEGF was correlated with poor
relapse-free survival
Reference: 1. Relf M, LeJeune S, Scott PA, et al. Cancer Res. 1997;57:963-969.
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The VEGF ligand is overexpressed in breast tumor tissue
Reprinted with permission from the American Association for Cancer Research.
Yoshiji H, Gomez DE, Shibuya M, Thorgeirsson UP. Cancer Res. 1996;56:2013-2016.
Yoshiji et al: VEGF overexpressed in breast tumor tissue compared with
surrounding normal tissue1
Reference: 1. Yoshiji H, Gomez DE, Shibuya M, Thorgeirsson UP. Cancer Res. 1996;56:2013-2016.
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The VEGF ligand is significant throughout
breast tumor development
Adapted from Folkman 2005.
VEGF appears to be the only pro-angiogenic factor expressed throughout the
breast tumor life cycle1
— The clinical significance of this finding is unknown
Reference: 1. Folkman J. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. Vol 2. 7th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2005:2865-2882.
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VEGF ligand expression is ubiquitous in multiple
forms of breast cancer
VEGF overexpression is observed across multiple forms of breast cancer1-5
Additional studies support a correlation between VEGF and breast cancer6,7
Inflammatory breast cancer is highly angiogenic8
— VEGF-C and VEGF-D are overexpressed in inflammatory breast cancer
References: 1. Foekens JA, Peters HA, Grebenchtchikov N, et al. Cancer Res. 2001;61:5407-5414. 2. Gasparini G, Toi M, Gion M, et al.
J Natl Cancer Inst. 1997;89:139-147. 3. Konecny GE, Meng YG, Untch M, et al. Clin Cancer Res. 2004;10:1706-1716. 4. Linderholm B,
Grankvist K, Wilking N, et al. J Clin Oncol. 2000;18:1423-1431. 5. Gasparini G, Toi M, Miceli R, et al. Cancer J Sci Am. 1999;5:101-111.
6. Brown LF, Berse B, Jackman RW, et al. Hum Pathol. 1995;26:86-91. 7. Jacobs EJ, Feigelson HS, Bain EB, et al. Breast Cancer Res.
2006;8:R22. 8. Van der Auwera I, Van Laere SJ, Van Den Eynden GG, et al. Clin Cancer Res. 2004;10:7965-7971.
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Effects of VEGF in breast cancer
beyond angiogenesis
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VEGF ligand may be involved in autocrine signaling
pathways
The role of VEGF in breast cancer may extend beyond angiogenesis1,2
Breast cancer cells have been shown to express both VEGF and VEGF
receptors1
Several possible mechanisms may be responsible for autocrine VEGF
signaling in breast cancer1
References: 1. Mercurio AM, Lipscomb EA, Bachelder RE. J Mammary Gland Biol Neoplasia. 2005;10:283-290. 2. Weigand M, Hantel P,
Kreienberg R, Waltenberger J. Angiogenesis. 2005;8:197-204.
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Prevalence of VEGF
in breast cancer
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The VEGF ligand is overexpressed
in the majority of breast tumors
Variable
Positive for VEGF165-206
Positive for VEGF121-206
Overall
74% (453/611)
59% (359/611)
HER-2/neu
Negative
Positive
71% (353/497)
88% (100/114)
55% (271/497)
77% (88/114)
Lymph nodes
Negative
Positive
72% (210/290)
75% (233/310)
53% (155/290)
63% (196/310)
Hormone-receptor status
Negative
Positive
80% (109/137)
72% (343/474)
73% (100/137)
55% (259/474)
Histology
Invasive ductal
Invasive lobular
78% (432/554)
22% (8/37)
61% (340/554)
19% (7/37)
Reprinted from Clin Cancer Res, Vol. 10, Konecny GE, Meng YG, Untch M, et al, 1706-1716, 2004, with permission from the American
Association for Cancer Research.
In a study of 611 patients, the majority of breast tumors expressed VEGF1
Reference: 1. Konecny GE, Meng YG, Untch M, et al. Clin Cancer Res. 2004;10:1706-1716.
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VEGF and metastasis
in breast cancer
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VEGF ligand and microvessel density are associated with
increased metastasis in breast cancer
Weidner N, Semple JP, Welch WR, Folkman J. N Engl J Med. 1991;324:1-8,
Copyright © 1991 Massachusetts Medical Society.
Angiogenesis has been directly assessed by measuring microvessel density
(new blood vessels per microscopic field)1
Microvessel count and density have been associated with breast cancer
metastases1,2
References: 1. Weidner N, Semple JP, Welch WR, Folkman J. N Engl J Med. 1991;324:1-8. 2. Toi M, Inada K, Suzuki H, Tominaga T.
Breast Cancer Res Treat. 1995;36:193-204.
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VEGF may be involved in breast cancer bone metastasis
VEGF may be involved in breast cancer
metastasis to bone1
— Aldridge et al showed that VEGF stimulated
monocyte differentiation into bone-resorbing
osteoclast-like cells
Adapted by permission from Macmillan Publishers Ltd: Br J Cancer. 2005;92:1531-1537.
© 2005.
Reference: 1. Aldridge SE, Lennard TW, Williams JR, Birch MA. Br J Cancer. 2005;92:1531-1537.
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VEGF as a prognostic and
predictive factor in breast cancer
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The VEGF ligand is correlated with poor survival in
breast cancer
Gasparini G, Toi M, Gion M, et al. Prognostic significance of vascular endothelial growth
factor protein in node-negative breast carcinoma. J Natl Cancer Inst. 1997;89(2):139-147.
Adapted by permission of Oxford University Press.
VEGF expression negatively correlates with relapse-free and overall survival1
Large prospective clinical studies are needed to better clarify the prognostic
role of VEGF in breast cancer
Reference: 1. Gasparini G, Toi M, Gion M, et al. J Natl Cancer Inst. 1997;89:139-147.
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The VEGF ligand and microvessel density are associated with
poor prognosis in breast cancer
Adapted from Toi 1995. Reproduced with permission from Breast Cancer
Research and Treatment.
VEGF expression correlates with
microvessel density in breast cancer1,2
Guidi AJ, Berry DA, Broadwater G, et al. Association of
angiogenesis in lymph node metastases with outcome of
breast cancer. J Natl Cancer Inst. 2000;92(6):486-492.
Adapted by permission of Oxford University Press.
Presence of microvascular “hot
spots” is associated with poor
disease-free and overall survival3
References: 1. Toi M, Inada K, Suzuki H, Tominaga T. Breast Cancer Res Treat. 1995;36:193-204. 2. Guidi AJ, Schnitt SJ, Fischer L, et al.
Cancer. 1997;80:1945-1953. 3. Guidi AJ, Berry DA, Broadwater G, et al. J Natl Cancer Inst. 2000;92:486-492.
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The VEGF ligand may predict response to systemic
therapy
A large clinical study has demonstrated
that VEGF expression is correlated with
poor response to systemic therapy1
— Tamoxifen (top image) or chemotherapy
(lower image)
Preclinical data indicate that VEGF may
contribute to hormone therapy resistance
and tumor progression2
In tumor cell lines, antihormones have
been shown to induce VEGF expression3
Reprinted with permission from the American Association for Cancer Research.
Foekens JA, Peters HA, Grebenchtchikov N, et al. Cancer Res. 2001;61:5407-5414.
References: 1. Foekens JA, Peters HA, Grebenchtchikov N, et al. Cancer Res. 2001;61:5407-5414. 2. Liang Y, Brekken RA, Hyder SM.
Endocr Rel Cancer. 2006;13:905-919. 3. Hyder SM. Endocr Rel Cancer. 2006;13:667-687.
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The VEGF ligand and other
common breast cancer tumor markers
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VEGF, estrogen, and estrogen receptor interactions
in breast cancer
VEGF may be regulated by hormones through autocrine and paracrine
mechanisms1
Buteau-Lozano et al demonstrated that estrogen modulates VEGF
expression at the gene transcriptional level1
VEGF levels have been associated with response to adjuvant anti-estrogen
therapy2
Although VEGF may be regulated by estrogen, VEGF expression has been
correlated with estrogen receptor (ER)–negative status3
— ER-negative status is associated with poor prognosis
References: 1. Buteau-Lozano H, Ancelin M, Lardeux B, et al. Cancer Res. 2002;62:4977-4984. 2. Linderholm B, Grankvist K, Wilking N,
et al. J Clin Oncol. 2000;18:1423-1431. 3. Fučkar D, Dekanić A, Štifter S, et al. Int J Surg Pathol. 2006;14:49-55.
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VEGF ligand and HER-2 in breast cancer: a positive
association
Preclinical research shows that overexpression of HER-2/neu results in
induction of the basal level of VEGF1
In a study of 611 patients, the poorest outcomes were seen in patients whose
tumors overexpressed both HER-2/neu and VEGF2
References: 1. Yen L, You XL, Al Moustafa AE, et al. Oncogene. 2000;19:3460-3469. 2. Konecny GE, Meng YG, Untch M, et al. Clin Cancer
Res. 2004;10:1706-1716.
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VEGF ligand secretion: linked to BRCA-1
BRCA-1 is a gene that increases risk of breast cancer1
— Normal BRCA-1 is involved in reparation of DNA breaks
— In mutated BRCA-1, DNA repair function is disabled
Preclinical research has shown that VEGF expression is mediated by a direct
interaction of BRCA-1 protein and ER1
— Normal BRCA-1 protein regulates VEGF expression and secretion
— Mutated BRCA-1 protein is unable to suppress VEGF expression
Reference: 1. Kawai H, Li H, Chun P, et al. Oncogene. 2002;21:7730-7739.
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The VEGF ligand in breast cancer: summary
VEGF appears to play a complex and critical role across many different
forms of breast cancer and throughout the course of a breast tumor
life cycle1-5
VEGF overexpression and/or angiogenesis have been observed to be
associated with increased metastasis and poor outcome1-4,6
VEGF and VEGF expression play a role in a complex relationship with other
breast cancer markers such as ER, BRCA-1 and, HER-2/neu2,3,7-9
New research continues to provide insight into the role of VEGF in
breast cancer
Large prospective studies are needed to better define the relationship of
prognosis with angiogenesis and VEGF
References: 1. Foekens JA, Peters HA, Grebenchtchikov N, et al. Cancer Res. 2001;61:5407-5414. 2. Gasparini G, Toi M, Gion M, et al.
J Natl Cancer Inst. 1997;89:139-147. 3. Konecny GE, Meng YG, Untch M, et al. Clin Cancer Res. 2004;10:1706-1716. 4. Linderholm B,
Grankvist K, Wilking N, et al. J Clin Oncol. 2000;18:1423-1431. 5. Folkman J. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer:
Principles and Practice of Oncology. Vol 2. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:2865-2882. 6. Weidner N,
Semple JP, Welch WR, Folkman J. N Engl J Med. 1991;324:1-8. 7. Buteau-Lozano H, Ancelin M, Lardeux B, et al. Cancer Res.
2002;62:4977-4984. 8. Fučkar D, Dekanić A, Štifter S, et al. Int J Surg Pathol. 2006;14:49-55. 9. Kawai H, Li H, Chun P, et al. Oncogene.
2002;21:7730-7739.
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