Yihai Cao Group

Our laboratory studies mechanisms of angiogenesis, the formation of blood vessels, under various physiological and pathological conditions. Since 2010, we have been actively working on tumor and adipose angiogenesis (see our reviews: Nat Rev Clin Oncol, 2010, PMID: 20683436; Nat Rev Drug Discov, 2010, PMID: 20118961; Sci Transl Med, 2010, PMID: 20371469; Sci Transl Med, 2011, PMID: 2219024, Cell Metabolism, 2013 PMID:  24035587;Nat Rev Endocrinol. 2014, PMID:  25048037). Several novel mechanisms affecting angiogenesis in the tumor microenvironment have been revealed, which regulate of tumor growth, invasion, metastasis and drug resistance. In particular, we have discovered erythropoietin as a new angiogenic molecule that mediates platelet derived growth factor-induced angiogenesis (Xue et al, Nature Medicine 2011, PMID:  22138754). This study provides a new mechanism of development of antiangiogenic cancer drug resistance.

In several preclinical tumor models, we have studied the mechanisms underlying antiangiogenic drug-related adverse effects. Systemic delivery of antiangiogenic drugs in mice results in marked vascular regression in several endocine organs (Proc Natl Acad Sci USA., 2013 PMID: 23818623) with prolonged treatment to cause detrimental effects on endocrine functions, leading to hypothyroidism, adrenal insufficiency and alterations of blood glucose levels. Interestingly, these endocrine disorders are commonly also observed in treated human cancer patients. Based on our studies, we propose several new concepts and hypotheses to rationally explain the mechanisms that underlie survival benefits of antiangiogenic therapy. We propose that off-tumor targets which lead to vascular normalization are potential beneficial sites of blood vessel cancer drugs (Nat Rev Clin Oncol, 2010, PMID: 20683436).

We also propose that reduction of chemotoxicity is another potential beneficial effect of addition of antiangiogenic components to standard chemotherapy (Proc Natl Acad Sci USA, 2011 PMID: 21367692). Recently, we discovered that cold exposure induces a browning phenotype (beige) in white adipose tissue. Importantly, clod activated beige adipose tissue-associated lipolysis markedly accelerates atherosclerotic plaque development in mice, raising the possibility of an increased cardiovascular risk (Dong et al, Cell Metabolism. 2013, PMID:  23823482). This study mechanistically explains why cold seasons are coupled to a high incidence of cardiovascular diseases. Also, we have found an angiogenesis-related mechanism of development of type 2diabetes in a high risk population of humans (Proc Natl Acad Sci USA, 2014 PMID: 25271320).We used zebrafish as a model to show that circadian clock controls developmental angiogenesis (Jensen et al, Cell Reports 2012,PMID: 22884368 ). Control of the biological clock may even regulate pathological angiogenesis such as tumor angiogenesis.

In collaboration with other scientists,  we have developed new assays by which drug targets can be studied in vivo (Molina et al, Science 2013,PMID: 23828940). Very recently, we have discovered that new mechanisms underlying lymphangiogenesis, cancer metastasis and drug responses. (Nature Communications, 2013, PMID: 23531851; Nature Communications, 2013, PMID: 25229256; Cell Reports, PMID:25310988). We hope that our translational angiogenesis research will lead to the development of novel and effective approaches for treatment of human cancer, obesity, diabetes, eye disease and chronic inflammation.

Projects

We are interested in studying the molecular mechanisms of the angiogenic switch in tumors and other diseases by characterizing the biological functions of a number of angiogenic factors and their signalling events.

Our research group is interested in studying the switch of the angiogenic phenotype in tumors by identification, isolation and characterization of novel angiogenesis regulators. Our ultimate goal is to develop strategies that could stop tumor growth and metastasis.

Studies of pro-angiogenic factors

We are studying the molecular mechanisms of angiogenesis and vascular permeability induced by the family of vascular endothelial growth factor (VEGF) which is overexpressed in virtually all types of tumors. We are characterizing the signal transduction events mediated by the VEGF receptors. We aim to develop VEGF antagonists and agonists that can be used for disease therapy. In addition, we have found that leptin, a hormone produced by fat tissue, induces angiogenesis. We are characterizing the signaling pathways induced by this novel angiogenic factor.

Further we are studying the role of angiogenesis in cardiovascular diseases. We are developing methods to use angiogenic factors to establish the alternative circulation pathways after heart attack. This work relates to a recently published project dealing with the stability of the established blood vessels.

Studies of anti-angiogenic factors

We are searching for potent angiogenesis inhibitors that can be used in cancer therapy. We are particularly interested in angiostatin and its related molecules that specifically target the newly formed blood vessels and have no effect on the existing vasculature. Previous studies have shown that angiostatin is a potent tumor suppressor. However, the only problem is that the dosage of angiostatin used in animal studies seems to be too high to be realistic in clinical trials. How do we overcome this problem in order to move the laboratory study to the bedside?

We have developed several alternative strategies that may allow us to overcome the problem. First, Renhai Cao and Niina Veitomäki have found a more potent molecule than angiostatin, namely kringle 1-5 (ref) of plasminogen that suppresses tumor growth in mice at low dosages. We are studying the molecular mechanisms of this novel angiogenesis inhibitor. We are also developing other therapeutic approaches for targeting the vascular compartment. These approaches include gene therapy, tumor targeting, slow release polymers and combinatorial therapy. In addition, we have identified several new angiogenic and antiangiogenic molecules that can be potentially used for disease therapy. These include VEGF-C (ref), leptin (ref), interleukin-18 (ref) and chemokines. The molecular mechanisms underlying how these inhibitors suppress angiogenesis are being studied.

Members in our group often drink green tea instead of coffee during our tea breaks. In fact, there are some good reasons to drink green tea because it contains a compound named epigallocatechin-3-gallate (EGCG), which has been reported to suppress the growth of a variety types of tumors in animals. We have recently found that drinking green tea suppresses angiogenesis in animal models (ref). Thus, drinking green tea may become beneficial not only for cancer prevention but also for prevention of other angiogenic diseases such as diabetes. We recommend you to begin drinking green tea for the benefit of your own health. You can contact Renhai for receiving samples of green tea.

Antiangiogenesis

We run several rigorous angiogenesis assays including the chick chorioallantoic membrane assay, the mouse corneal micropocket assay, the endothelial cell growth (proliferation) assay, the endothelial motility assay and the tumor angiogenesis assay. If you have some molecules that may be involved in regulation of angiogenesis, you are welcome to contact Dr. Yihai Cao.

Publications

2016

Co-option of pre-existing vascular beds in adipose tissue controls tumor growth rates and angiogenesis.
Lim S, Hosaka K, Nakamura M, Cao Y
Oncotarget 2016 May;():

The PDGF-BB-SOX7 axis-modulated IL-33 in pericytes and stromal cells promotes metastasis through tumour-associated macrophages.
Yang Y, Andersson P, Hosaka K, Zhang Y, Cao R, Iwamoto H, et al
Nat Commun 2016 ;7():11385

Endocrine vasculatures are preferable targets of an antitumor ineffective low dose of anti-VEGF therapy.
Zhang Y, Yang Y, Hosaka K, Huang G, Zang J, Chen F, et al
Proc. Natl. Acad. Sci. U.S.A. 2016 Apr;113(15):4158-63

Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE.
Carmona G, Perera U, Gillett C, Naba A, Law A, Sharma V, et al
Oncogene 2016 Mar;():

MT1-MMP sheds LYVE-1 on lymphatic endothelial cells and suppresses VEGF-C production to inhibit lymphangiogenesis.
Wong H, Jin G, Cao R, Zhang S, Cao Y, Zhou Z
Nat Commun 2016 ;7():10824

Future options of anti-angiogenic cancer therapy.
Cao Y
Chin J Cancer 2016 ;35(1):21

Resveratrol analogue 4,4'-dihydroxy-trans-stilbene potently inhibits cancer invasion and metastasis.
Savio M, Ferraro D, Maccario C, Vaccarone R, Jensen L, Corana F, et al
Sci Rep 2016 ;6():19973

2015

VEGF-B-Neuropilin-1 signaling is spatiotemporally indispensable for vascular and neuronal development in zebrafish.
Jensen L, Nakamura M, Bräutigam L, Li X, Liu Y, Samani N, et al
Proc. Natl. Acad. Sci. U.S.A. 2015 Nov;112(44):E5944-53

Environmental changes in oxygen tension reveal ROS-dependent neurogenesis and regeneration in the adult newt brain.
Hameed L, Berg D, Belnoue L, Jensen L, Cao Y, Simon A
Elife 2015 ;4():

Invasiveness and metastasis of retinoblastoma in an orthotopic zebrafish tumor model.
Chen X, Wang J, Cao Z, Hosaka K, Jensen L, Yang H, et al
Sci Rep 2015 ;5():10351

VEGF-B promotes cancer metastasis through a VEGF-A-independent mechanism and serves as a marker of poor prognosis for cancer patients.
Yang X, Zhang Y, Hosaka K, Andersson P, Wang J, Tholander F, et al
Proc. Natl. Acad. Sci. U.S.A. 2015 Jun;112(22):E2900-9

CCL2 and CCL5 Are Novel Therapeutic Targets for Estrogen-Dependent Breast Cancer.
Svensson S, Abrahamsson A, Rodriguez G, Olsson A, Jensen L, Cao Y, et al
Clin. Cancer Res. 2015 Aug;21(16):3794-805

PlGF-induced VEGFR1-dependent vascular remodeling determines opposing antitumor effects and drug resistance to Dll4-Notch inhibitors.  Hideki Iwamoto, Yin Zhang, Takahiro Seki, Yunlong Yang, Masaki Nakamura, Jian Wang, Xiaojuan Yang, Takuji Torimura, Yihai Cao. Science Advances 10 Apr 2015: Vol. 1 no. 3 e1400244 DOI: 10.1126/sciadv.1400244

2014

MicroRNA-206 functions as a pleiotropic modulator of cell proliferation, invasion and lymphangiogenesis in pancreatic adenocarcinoma by targeting ANXA2 and KRAS genes.
Keklikoglou I, Hosaka K, Bender C, Bott A, Koerner C, Mitra D, et al
Oncogene 2015 Sep;34(37):4867-78

Hypoxic regulation of RIOK3 is a major mechanism for cancer cell invasion and metastasis.
Singleton D, Rouhi P, Zois C, Haider S, Li J, Kessler B, et al
Oncogene 2015 Sep;34(36):4713-22

Novel mechanism of macrophage-mediated metastasis revealed in a zebrafish model of tumor development.
Wang J, Cao Z, Zhang X, Nakamura M, Sun M, Hartman J, et al
Cancer Res. 2015 Jan;75(2):306-15

VEGFR2-mediated vascular dilation as a mechanism of VEGF-induced anemia and bone marrow cell mobilization.
Lim S, Zhang Y, Zhang D, Chen F, Hosaka K, Feng N, et al
Cell Rep 2014 Oct;9(2):569-80

Modulation of age-related insulin sensitivity by VEGF-dependent vascular plasticity in adipose tissues.
Honek J, Seki T, Iwamoto H, Fischer C, Li J, Lim S, et al
Proc. Natl. Acad. Sci. U.S.A. 2014 Oct;111(41):14906-11

Vasoprotective effect of PDGF-CC mediated by HMOX1 rescues retinal degeneration.
He C, Zhao C, Kumar A, Lee C, Chen M, Huang L, et al
Proc. Natl. Acad. Sci. U.S.A. 2014 Oct;111(41):14806-11

TNFR1 mediates TNF-α-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling.
Ji H, Cao R, Yang Y, Zhang Y, Iwamoto H, Lim S, et al
Nat Commun 2014 ;5():4944

VEGF-targeted cancer therapeutics-paradoxical effects in endocrine organs.
Cao Y
Nat Rev Endocrinol 2014 Sep;10(9):530-9

Genome-wide profiling of AP-1-regulated transcription provides insights into the invasiveness of triple-negative breast cancer.
Zhao C, Qiao Y, Jonsson P, Wang J, Xu L, Rouhi P, et al
Cancer Res. 2014 Jul;74(14):3983-94

Hypoxia-induced and calpain-dependent cleavage of filamin A regulates the hypoxic response.
Zheng X, Zhou A, Rouhi P, Uramoto H, Borén J, Cao Y, et al
Proc. Natl. Acad. Sci. U.S.A. 2014 Feb;111(7):2560-5

Mutant p53-associated myosin-X upregulation promotes breast cancer invasion and metastasis.
Arjonen A, Kaukonen R, Mattila E, Rouhi P, Högnäs G, Sihto H, et al
J. Clin. Invest. 2014 Mar;124(3):1069-82

2013

Angiostatic effects of NK cell-derived IFN-γ counteracted by tumour cell Bcl-xL expression.
Wallin R, Sundquist V, Bråkenhielm E, Cao Y, Ljunggren H, Grandien A
Scand. J. Immunol. 2014 Feb;79(2):90-7

Glutaredoxin regulates vascular development by reversible glutathionylation of sirtuin 1.
Bräutigam L, Jensen L, Poschmann G, Nyström S, Bannenberg S, Dreij K, et al
Proc. Natl. Acad. Sci. U.S.A. 2013 Dec;110(50):20057-62

Angiogenesis as a therapeutic target for obesity and metabolic diseases.
Cao Y
Chem Immunol Allergy 2014 ;99():170-9

Angiogenesis and vascular functions in modulation of obesity, adipose metabolism, and insulin sensitivity.
Cao Y
Cell Metab. 2013 Oct;18(4):478-89

Vascular endothelial growth factor-dependent spatiotemporal dual roles of placental growth factor in modulation of angiogenesis and tumor growth.
Yang X, Zhang Y, Yang Y, Lim S, Cao Z, Rak J, et al
Proc. Natl. Acad. Sci. U.S.A. 2013 Aug;110(34):13932-7

Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis.
Hosaka K, Yang Y, Seki T, Nakamura M, Andersson P, Rouhi P, et al
Nat Commun 2013 ;4():2129

Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay.
Martinez Molina D, Jafari R, Ignatushchenko M, Seki T, Larsson E, Dan C, et al
Science 2013 Jul;341(6141):84-7

Cold exposure promotes atherosclerotic plaque growth and instability via UCP1-dependent lipolysis.
Dong M, Yang X, Lim S, Cao Z, Honek J, Lu H, et al
Cell Metab. 2013 Jul;18(1):118-29

Anti-VEGF- and anti-VEGF receptor-induced vascular alteration in mouse healthy tissues.
Yang Y, Zhang Y, Cao Z, Ji H, Yang X, Iwamoto H, et al
Proc. Natl. Acad. Sci. U.S.A. 2013 Jul;110(29):12018-23

Multifarious functions of PDGFs and PDGFRs in tumor growth and metastasis.
Cao Y
Trends Mol Med 2013 Aug;19(8):460-73

Clock controls angiogenesis.
Jensen L, Cao Y
Cell Cycle 2013 Feb;12(3):405-8

2012

Tumor cell-derived placental growth factor sensitizes antiangiogenic and antitumor effects of anti-VEGF drugs.
Hedlund E, Yang X, Zhang Y, Yang Y, Shibuya M, Zhong W, et al
Proc. Natl. Acad. Sci. U.S.A. 2013 Jan;110(2):654-9

Erythropoietin in cancer: a dilemma in risk therapy.
Cao Y
Trends Endocrinol. Metab. 2013 Apr;24(4):190-9

Proliferative and survival effects of PUMA promote angiogenesis.
Zhang F, Li Y, Tang Z, Kumar A, Lee C, Zhang L, et al
Cell Rep 2012 Nov;2(5):1272-85

Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis.
Cao R, Ji H, Feng N, Zhang Y, Yang X, Andersson P, et al
Proc. Natl. Acad. Sci. U.S.A. 2012 Sep;109(39):15894-9

Opposing effects of circadian clock genes bmal1 and period2 in regulation of VEGF-dependent angiogenesis in developing zebrafish.
Jensen L, Cao Z, Nakamura M, Yang Y, Bräutigam L, Andersson P, et al
Cell Rep 2012 Aug;2(2):231-41

Targeting filamin A reduces K-RAS-induced lung adenocarcinomas and endothelial response to tumor growth in mice.
Nallapalli R, Ibrahim M, Zhou A, Bandaru S, Sunkara S, Redfors B, et al
Mol. Cancer 2012 ;11():50

When MT1-MMP meets ADAMs.
Wong H, Cao R, Jin G, Chan K, Cao Y, Zhou Z
Cell Cycle 2012 Aug;11(15):2793-8

MT1-MMP inactivates ADAM9 to regulate FGFR2 signaling and calvarial osteogenesis.
Chan K, Wong H, Jin G, Liu B, Cao R, Cao Y, et al
Dev. Cell 2012 Jun;22(6):1176-90

Cold-induced activation of brown adipose tissue and adipose angiogenesis in mice.
Lim S, Honek J, Xue Y, Seki T, Cao Z, Andersson P, et al
Nat Protoc 2012 Mar;7(3):606-15

2011

Forty-year journey of angiogenesis translational research.
Cao Y, Arbiser J, D'Amato R, D'Amore P, Ingber D, Kerbel R, et al
Sci Transl Med 2011 Dec;3(114):114rv3

PDGF-BB modulates hematopoiesis and tumor angiogenesis by inducing erythropoietin production in stromal cells.
Xue Y, Lim S, Yang Y, Wang Z, Jensen L, Hedlund E, et al
Nat. Med. 2012 Jan;18(1):100-10

Arteriogenic therapy by intramyocardial sustained delivery of a novel growth factor combination prevents chronic heart failure.
Banquet S, Gomez E, Nicol L, Edwards-Lévy F, Henry J, Cao R, et al
Circulation 2011 Aug;124(9):1059-69

It's hard to keep all things angiogenic in one JAR!
Kitajewski J, Cao Y, Slevin M
2011 ;3(1):1

Zebrafish models to study hypoxia-induced pathological angiogenesis in malignant and nonmalignant diseases.
Jensen L, Rouhi P, Cao Z, Länne T, Wahlberg E, Cao Y
Birth Defects Res. C Embryo Today 2011 Jun;93(2):182-93

Mouse corneal lymphangiogenesis model.
Cao R, Lim S, Ji H, Zhang Y, Yang Y, Honek J, et al
Nat Protoc 2011 Jun;6(6):817-26

Antiangiogenic agents significantly improve survival in tumor-bearing mice by increasing tolerance to chemotherapy-induced toxicity.
Zhang D, Hedlund E, Lim S, Chen F, Zhang Y, Sun B, et al
Proc. Natl. Acad. Sci. U.S.A. 2011 Mar;108(10):4117-22

2010

Hypoxia-induced metastasis model in embryonic zebrafish.
Rouhi P, Jensen L, Cao Z, Hosaka K, Länne T, Wahlberg E, et al
Nat Protoc 2010 Dec;5(12):1911-8

Hypoxia-induced retinopathy model in adult zebrafish.
Cao Z, Jensen L, Rouhi P, Hosaka K, Länne T, Steffensen J, et al
Nat Protoc 2010 Dec;5(12):1903-10

Angiotensin-converting enzyme 2 attenuates atherosclerotic lesions by targeting vascular cells.
Zhang C, Zhao Y, Zhang Y, Zhu L, Deng B, Zhou Z, et al
Proc. Natl. Acad. Sci. U.S.A. 2010 Sep;107(36):15886-91

Off-tumor target--beneficial site for antiangiogenic cancer therapy?
Cao Y
Nat Rev Clin Oncol 2010 Oct;7(10):604-8

PDGF-CC blockade inhibits pathological angiogenesis by acting on multiple cellular and molecular targets.
Hou X, Kumar A, Lee C, Wang B, Arjunan P, Dong L, et al
Proc. Natl. Acad. Sci. U.S.A. 2010 Jul;107(27):12216-21

Cancer-associated retinopathy: a new mechanistic insight on vascular remodeling.
Cao R, Cao Y
Cell Cycle 2010 May;9(10):1882-5

Adipose angiogenesis: quantitative methods to study microvessel growth, regression and remodeling in vivo.
Xue Y, Lim S, Bråkenhielm E, Cao Y
Nat Protoc 2010 May;5(5):912-20

Wake-up call for endothelial cells.
Cao Y
Blood 2010 Mar;115(12):2336-7

Survival effect of PDGF-CC rescues neurons from apoptosis in both brain and retina by regulating GSK3beta phosphorylation.
Tang Z, Arjunan P, Lee C, Li Y, Kumar A, Hou X, et al
J. Exp. Med. 2010 Apr;207(4):867-80

Therapeutic angiogenesis for ischemic disorders: what is missing for clinical benefits?
Cao Y
Discov Med 2010 Mar;9(46):179-84

Angiogenesis: What can it offer for future medicine?
Cao Y
Exp. Cell Res. 2010 May;316(8):1304-8

Pathological angiogenesis facilitates tumor cell dissemination and metastasis.
Rouhi P, Lee S, Cao Z, Hedlund E, Jensen L, Cao Y
Cell Cycle 2010 Mar;9(5):913-7

Adipose tissue angiogenesis as a therapeutic target for obesity and metabolic diseases.
Cao Y
Nat Rev Drug Discov 2010 Feb;9(2):107-15

Optimizing the delivery of cancer drugs that block angiogenesis.
Cao Y, Langer R
Sci Transl Med 2010 Jan;2(15):15ps3

VEGFR1-mediated pericyte ablation links VEGF and PlGF to cancer-associated retinopathy.
Cao R, Xue Y, Hedlund E, Zhong Z, Tritsaris K, Tondelli B, et al
Proc. Natl. Acad. Sci. U.S.A. 2010 Jan;107(2):856-61

 

Older Publications

yihai_cao_publications 2009.pdf

yihai_cao_publications2000-2008.pdf

yihai_cao_full_publications.pdf

 

Group Members

Professor

Yihai Cao

Phone: 08-524 875 96
Organizational unit: Yihai Cao group
E-mail: Yihai.Cao@ki.se

Associated

Linlin Yin

E-mail: linlin.yin@ki.se

Caifeng LiuAssociated
Carina FischerPhD student, Graduate Student
Dongmei CuiAssociated
Kayoko HosakaSenior lab manager
Lasse JensenAssociated
Li ChenBiomedical scientist
Linlin YinAssociated
Masaki NakamuraPostdoc
Mitsuhiko AbePostdoc
Patrik AnderssonPhD student, Graduate Student
Qinghua LaiAssociated
Renhai CaoSenior researcher
Sharon LimPostdoc
Takahiro SekiSenior lab manager
Xiaoli HuiAssociated
Yihai CaoProfessor
Yin ZhangPostdoc
Yunjian ZhangAssociated
Yunlong YangPostdoc

 

Former Members

Former Group Members

Links