liu.seSearch for publications in DiVA
Change search
Link to record
Permanent link

Direct link
BETA
Cao, Yihai
Publications (10 of 37) Show all publications
Lim, S., Hosaka, K., Nakamura, M. & Cao, Y. (2016). Co-option of pre-existing vascular beds in adipose tissue controls tumor growth rates and angiogenesis. OncoTarget, 7(25), 38282-38291
Open this publication in new window or tab >>Co-option of pre-existing vascular beds in adipose tissue controls tumor growth rates and angiogenesis
2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 25, p. 38282-38291Article in journal (Refereed) Published
Abstract [en]

Many types of cancer develop in close association with highly vascularized adipose tissues. However, the role of adipose pre-existing vascular beds on tumor growth and angiogenesis is unknown. Here we report that pre-existing microvascular density in tissues where tumors originate is a crucial determinant for tumor growth and neovascularization. In three independent tumor types including breast cancer, melanoma, and fibrosarcoma, inoculation of tumor cells in the subcutaneous tissue, white adipose tissue (WAT), and brown adipose tissue (BAT) resulted in markedly differential tumor growth rates and angiogenesis, which were in concordance with the degree of pre-existing vascularization in these tissues. Relative to subcutaneous tumors, WAT and BAT tumors grew at accelerated rates along with improved neovascularization, blood perfusion, and decreased hypoxia. Tumor cells implanted in adipose tissues contained leaky microvessel with poor perivascular cell coverage. Thus, adipose vasculature predetermines the tumor microenvironment that eventually supports tumor growth.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2016
Keywords
adipose tissue; angiogenesis; tumor growth; vasculature; microenvironment
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-130281 (URN)10.18632/oncotarget.9436 (DOI)000378229100069 ()27203675 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Cancer Foundation; Karolinska Institute Foundation; Karolinska Institute; Torsten Soderbergs foundation; European Research Council (ERC) advanced grant ANGIOFAT [250021]; Knut Alice Wallenberg Foundation; Novo Nordisk Foundation; Alex and Eva Wallstroms foundation; Lars Hiertas Minne foundation

Available from: 2016-08-01 Created: 2016-07-28 Last updated: 2017-11-28
Zhang, Y., Yang, Y., Hosaka, K., Huang, G., Zang, J., Chen, F., . . . Cao, Y. (2016). Endocrine vasculatures are preferable targets of an antitumor ineffective low dose of anti-VEGF therapy. Proceedings of the National Academy of Sciences of the United States of America, 113(15), 4158-4163
Open this publication in new window or tab >>Endocrine vasculatures are preferable targets of an antitumor ineffective low dose of anti-VEGF therapy
Show others...
2016 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 15, p. 4158-4163Article in journal (Refereed) Published
Abstract [en]

Anti-VEGF-based antiangiogenic drugs are designed to block tumor angiogenesis for treatment of cancer patients. However, anti-VEGF drugs produce off-tumor target effects on multiple tissues and organs and cause broad adverse effects. Here, we show that vasculatures in endocrine organs were more sensitive to anti-VEGF treatment than tumor vasculatures. In thyroid, adrenal glands, and pancreatic islets, systemic treatment with low doses of an anti-VEGF neutralizing antibody caused marked vascular regression, whereas tumor vessels remained unaffected. Additionally, a low dose of VEGF blockade significantly inhibited the formation of thyroid vascular fenestrae, leaving tumor vascular structures unchanged. Along with vascular structural changes, the low dose of VEGF blockade inhibited vascular perfusion and permeability in thyroid, but not in tumors. Prolonged treatment with the low-dose VEGF blockade caused hypertension and significantly decreased circulating levels of thyroid hormone free-T3 and -T4, leading to functional impairment of thyroid. These findings show that the fenestrated microvasculatures in endocrine organs are more sensitive than tumor vasculatures in response to systemic anti-VEGF drugs. Thus, our data support the notion that clinically nonbeneficial treatments with anti-VEGF drugs could potentially cause adverse effects.

Place, publisher, year, edition, pages
NATL ACAD SCIENCES, 2016
Keywords
tumor; angiogenesis; VEGF; antiangiogenic therapy; adverse effects
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-127551 (URN)10.1073/pnas.1601649113 (DOI)000373762400067 ()27035988 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Cancer Foundation; Swedish Diabetes Research Foundation; Swedish Childhood Cancer Foundation; Karolinska Institute Foundation; Karolinska Institute Distinguished Professor award; Torsten Soderbergs Foundation; European Research Council Advanced Grant ANGIOFAT [250021]; Knut Alice Wallenberg Foundation; Program of Introducing Talents of Discipline to Universities [B07035]; State Program of National Natural Science Foundation of China for Innovative Research Group [81321061]; NOVO Nordisk Foundation for the advanced grant

Available from: 2016-05-04 Created: 2016-05-03 Last updated: 2017-05-02
Cao, Y. (2016). Future options of anti-angiogenic cancer therapy. CHINESE JOURNAL OF CANCER, 35(21)
Open this publication in new window or tab >>Future options of anti-angiogenic cancer therapy
2016 (English)In: CHINESE JOURNAL OF CANCER, ISSN 1000-467X, Vol. 35, no 21Article, review/survey (Refereed) Published
Abstract [en]

In human patients, drugs that block tumor vessel growth are widely used to treat a variety of cancer types. Many rigorous phase 3 clinical trials have demonstrated significant survival benefits; however, the addition of an anti-angiogenic component to conventional therapeutic modalities has generally produced modest survival benefits for cancer patients. Currently, it is unclear why these clinically available drugs targeting the same angiogenic pathways produce dissimilar effects in preclinical models and human patients. In this article, we discuss possible mechanisms of various anti-angiogenic drugs and the future development of optimized treatment regimens.

Place, publisher, year, edition, pages
SUN YAT SEN UNIV MED SCI WHO, 2016
Keywords
Angiogenesis; Cancer therapy; Anti-angiogenesis; Vascular endothelial growth factor; Biomarker
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-125802 (URN)10.1186/s40880-016-0084-4 (DOI)000370009400002 ()26879126 (PubMedID)
Note

Funding Agencies|European Research Council advanced grant ANGIOFAT [250021]; Swedish Research Council; Swedish Cancer Foundation; Karolinska Institute Foundation; Karolinska Institute Distinguished Professor Award; Torsten Soderberg Foundation; Novo Nordisk Foundation; Knut and Alice Wallenberg Foundation

Available from: 2016-03-08 Created: 2016-03-04 Last updated: 2017-05-02
Yang, Y., Andersson, P., Hosaka, K., Zhang, Y., Cao, R., Iwamoto, H., . . . Cao, Y. (2016). The PDGF-BB-SOX7 axis-modulated IL-33 in pericytes and stromal cells promotes metastasis through tumour-associated macrophages. Nature Communications, 7(11385)
Open this publication in new window or tab >>The PDGF-BB-SOX7 axis-modulated IL-33 in pericytes and stromal cells promotes metastasis through tumour-associated macrophages
Show others...
2016 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, no 11385Article in journal (Refereed) Published
Abstract [en]

Signalling molecules and pathways that mediate crosstalk between various tumour cellular compartments in cancer metastasis remain largely unknown. We report a mechanism of the interaction between perivascular cells and tumour-associated macrophages (TAMs) in promoting metastasis through the IL-33-ST2-dependent pathway in xenograft mouse models of cancer. IL-33 is the highest upregulated gene through activation of SOX7 transcription factor in PDGF-BB-stimulated pericytes. Gain-and loss-of-function experiments validate that IL-33 promotes metastasis through recruitment of TAMs. Pharmacological inhibition of the IL-33-ST2 signalling by a soluble ST2 significantly inhibits TAMs and metastasis. Genetic deletion of host IL-33 in mice also blocks PDGF-BB-induced TAM recruitment and metastasis. These findings shed light on the role of tumour stroma in promoting metastasis and have therapeutic implications for cancer therapy.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2016
National Category
Basic Medicine
Identifiers
urn:nbn:se:liu:diva-128743 (URN)10.1038/ncomms11385 (DOI)000375491600001 ()27150562 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Cancer Foundation; Karolinska Institute Foundation; Karolinska Institute distinguished professor award; Torsten Soderbergs foundation; Tore Nilsons foundation; Martin Rinds foundation; European Research Council (ERC) advanced grant ANGIOFAT [250021]; NOVO Nordisk Foundation

Available from: 2016-05-31 Created: 2016-05-30 Last updated: 2018-03-27
Svensson, S., Abrahamsson, A., Vazquez Rodriguez, G., Olsson, A.-K., Jensen, L., Cao, Y. & Dabrosin, C. (2015). CCL2 and CCL5 Are Novel Therapeutic Targets for Estrogen-Dependent Breast Cancer. Clinical Cancer Research, 21(16), 3794-3805
Open this publication in new window or tab >>CCL2 and CCL5 Are Novel Therapeutic Targets for Estrogen-Dependent Breast Cancer
Show others...
2015 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 21, no 16, p. 3794-3805Article in journal (Refereed) Published
Abstract [en]

Purpose: Novel therapeutic targets of estrogen receptor (ER)-positive breast cancers are urgently needed because current antiestrogen therapy causes severe adverse effects, nearly 50% of patients are intrinsically resistant, and the majority of recurrences have maintained ER expression. We investigated the role of estrogen-dependent chemokine expression and subsequent cancer growth in human tissues and experimental breast cancer models. Experimental Design: For in vivo sampling of human chemokines, microdialysis was used in breast cancers of women or normal human breast tissue before and after tamoxifen therapy. Estrogen exposure and targeted therapies were assessed in immune competent PyMT murine breast cancer, orthotopic human breast cancers in nude mice, cell culture of cancer cells, and freshly isolated human macrophages. Cancer cell dissemination was investigated using zebrafish. Results: ER+ cancers in women produced high levels of extracellular CCL2 and CCL5 in vivo, which was associated with infiltration of tumor-associated macrophages. In experimental breast cancer, estradiol enhanced macrophage influx and angiogenesis through increased release of CCL2, CCL5, and vascular endothelial growth factor. These effects were inhibited by anti-CCL2 or anti-CCL5 therapy, which resulted in potent inhibition of cancer growth. In addition, estradiol induced a protumorigenic activation of the macrophages. In a zebrafish model, macrophages increased cancer cell dissemination via CCL2 and CCL5 in the presence of estradiol, which was inhibited with anti-CCL2 and anti-CCL5 treatment. Conclusions: Our findings shed new light on the mechanisms underlying the progression of ER+ breast cancer and indicate the potential of novel therapies targeting CCL2 and CCL5 pathways. (C)2015 AACR.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH, 2015
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-122122 (URN)10.1158/1078-0432.CCR-15-0204 (DOI)000361909100027 ()25901081 (PubMedID)
Note

Funding Agencies|Swedish Cancer Society [2009/799]; Swedish Research Council [2010-3458]; LiU-Cancer; Linkoping University Hospital

Available from: 2015-10-19 Created: 2015-10-19 Last updated: 2017-12-01
Cao, R., Ji, H., Yang, Y. & Cao, Y. (2015). Editorial Material: Collaborative effects between the TNF alpha-TNFR1-macrophage axis and the VEGF-C-VEGFR3 signaling in lymphangiogenesis and metastasis in ONCOIMMUNOLOGY, vol 4, issue 3, pp. Oncoimmunology, 4(3), e989777
Open this publication in new window or tab >>Editorial Material: Collaborative effects between the TNF alpha-TNFR1-macrophage axis and the VEGF-C-VEGFR3 signaling in lymphangiogenesis and metastasis in ONCOIMMUNOLOGY, vol 4, issue 3, pp
2015 (English)In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 4, no 3, p. e989777-Article in journal, Editorial material (Other academic) Published
Abstract [en]

Although inflammation and metastasis are two well-known hallmarks of malignant disease, the relationship between inflammation and lymphatic metastasis is an unexplored research area. We recently elucidated a sophisticated mechanism by which TNF alpha-induced tumor inflammation conscripts macrophage-mediated VEGF-C-VEGFR3 signaling in lymphangiogenesis and metastasis.

Place, publisher, year, edition, pages
TAYLOR and FRANCIS INC, 2015
Keywords
TNF-alpha; macrophage; inflammation; lymphangiogenesis; metastasis
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-117810 (URN)10.4161/2162402X.2014.989777 (DOI)000352612900018 ()25949904 (PubMedID)
Available from: 2015-05-11 Created: 2015-05-08 Last updated: 2017-12-04
Shahul Hameed, L., Berg, D. A., Belnoue, L., Jensen, L., Cao, Y. & Simon, A. (2015). Environmental changes in oxygen tension reveal ROS-dependent neurogenesis and regeneration in the adult newt brain. eLIFE, 4(e08422)
Open this publication in new window or tab >>Environmental changes in oxygen tension reveal ROS-dependent neurogenesis and regeneration in the adult newt brain
Show others...
2015 (English)In: eLIFE, E-ISSN 2050-084X, ELIFE SCIENCES PUBLICATIONS LTD, SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND, ISSN 2050-084X, Vol. 4, no e08422Article in journal (Refereed) Published
Abstract [en]

Organisms need to adapt to the ecological constraints in their habitat. How specific processes reflect such adaptations are difficult to model experimentally. We tested whether environmental shifts in oxygen tension lead to events in the adult newt brain that share features with processes occurring during neuronal regeneration under normoxia. By experimental simulation of varying oxygen concentrations, we show that hypoxia followed by re-oxygenation lead to neuronal death and hallmarks of an injury response, including activation of neural stem cells ultimately leading to neurogenesis. Neural stem cells accumulate reactive oxygen species (ROS) during re-oxygenation and inhibition of ROS biosynthesis counteracts their proliferation as well as neurogenesis. Importantly, regeneration of dopamine neurons under normoxia also depends on ROS-production. These data demonstrate a role for ROS-production in neurogenesis in newts and suggest that this role may have been recruited to the capacity to replace lost neurons in the brain of an adult vertebrate.

Place, publisher, year, edition, pages
ELIFE SCIENCES PUBLICATIONS LTD, 2015
Keywords
cell biology; developmental biology; neural stem cells; neurogenesis; newt; reactive oxygen species; regeneration; stem cells
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-127595 (URN)10.7554/eLife.08422 (DOI)000373886700001 ()26485032 (PubMedID)
Note

Funding Agencies|European Research Council (ERC); AFA Forsakring; Vetenskapsradet; Cancerfonden; Torsten Soderbergs Stiftelse; Novo Nordisk

Available from: 2016-05-03 Created: 2016-05-03 Last updated: 2018-01-10
Singleton, D. C., Rouhi, P., Zois, C. E., Haider, S., Li, J.-L., Kessler, B. M., . . . Harris, A. L. (2015). Hypoxic regulation of RIOK3 is a major mechanism for cancer cell invasion and metastasis. Oncogene, 34(36), 4713-4722
Open this publication in new window or tab >>Hypoxic regulation of RIOK3 is a major mechanism for cancer cell invasion and metastasis
Show others...
2015 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 34, no 36, p. 4713-4722Article in journal (Refereed) Published
Abstract [en]

Hypoxia is a common feature of locally advanced breast cancers that is associated with increased metastasis and poorer survival. Stabilisation of hypoxia-inducible factor-1 alpha (HIF1 alpha) in tumours causes transcriptional changes in numerous genes that function at distinct stages of the metastatic cascade. We demonstrate that expression of RIOK3 (RIght Open reading frame kinase 3) was increased during hypoxic exposure in an HIF1 alpha-dependent manner. RIOK3 was localised to distinct cytoplasmic aggregates in normoxic cells and underwent redistribution to the leading edge of the cell in hypoxia with a corresponding change in the organisation of the actin cytoskeleton. Depletion of RIOK3 expression caused MDA-MB-231 to become elongated and this morphological change was due to a loss of protraction at the trailing edge of the cell. This phenotypic change resulted in reduced cell migration in two-dimensional cultures and inhibition of cell invasion through three-dimensional extracellular matrix. Proteomic analysis identified interactions of RIOK3 with actin and several actin-binding factors including tropomyosins (TPM3 and TPM4) and tropomodulin 3. Depletion of RIOK3 in cells resulted in fewer and less organised actin filaments. Analysis of these filaments showed reduced association of TPM3, particularly during hypoxia, suggesting that RIOK3 regulates actin filament specialisation. RIOK3 depletion reduced the dissemination of MDA-MB-231 cells in both a zebrafish model of systemic metastasis and a mouse model of pulmonary metastasis. These findings demonstrate that RIOK3 is necessary for maintaining actin cytoskeletal organisation required for migration and invasion, biological processes that are necessary for hypoxia-driven metastasis.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2015
National Category
Basic Medicine
Identifiers
urn:nbn:se:liu:diva-121749 (URN)10.1038/onc.2014.396 (DOI)000360931500005 ()25486436 (PubMedID)
Note

Funding Agencies|European Commission Metoxia [222741]; British Columbia Cancer Agency Branch; Cancer Research UK

Available from: 2015-10-06 Created: 2015-10-05 Last updated: 2018-01-11
Chen, X., Wang, J., Cao, Z., Hosaka, K., Jensen, L., Yang, H., . . . Cao, Y. (2015). Invasiveness and metastasis of retinoblastoma in an orthotopic zebrafish tumor model. Scientific Reports, 5(10351)
Open this publication in new window or tab >>Invasiveness and metastasis of retinoblastoma in an orthotopic zebrafish tumor model
Show others...
2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, no 10351Article in journal (Refereed) Published
Abstract [en]

Retinoblastoma is a highly invasive malignant tumor that often invades the brain and metastasizes to distal organs through the blood stream. Invasiveness and metastasis of retinoblastoma can occur at the early stage of tumor development. However, an optimal preclinical model to study retinoblastoma invasiveness and metastasis in relation to drug treatment has not been developed. Here, we developed an orthotopic zebrafish model in which retinoblastoma invasion and metastasis can be monitored at a single cell level. We took the advantages of immune privilege and transparent nature of developing zebrafish embryos. Intravitreal implantation of color-coded retinoblastoma cells allowed us to kinetically monitor tumor cell invasion and metastasis. Further, interactions between retinoblastoma cells and surrounding microvasculatures were studied using a transgenic zebrafish that exhibited green fluorescent signals in blood vessels. We discovered that tumor cells invaded neighboring tissues and blood stream when primary tumors were at the microscopic sizes. These findings demonstrate that retinoblastoma metastasis occurs at the early stage and antiangiogenic drugs such as Vegf morpholino and sunitinib could potentially interfere with tumor invasiveness and metastasis. Thus, this orthotopic retinoblastoma model offers a new and unique opportunity to study the early events of tumor invasion, metastasis and drug responses.

Place, publisher, year, edition, pages
Nature Publishing Group: Open Access Journals - Option C / Nature Publishing Group, 2015
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-120338 (URN)10.1038/srep10351 (DOI)000357861300001 ()26169357 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Cancer Foundation; Karolinska Institute Foundation; Karolinska Institute distinguished professor award; Torsten Soderbergs foundation; Novo Nordisk Foundation; European Research Council (ERC) advanced grant ANGIOFAT [250021]

Available from: 2015-07-31 Created: 2015-07-31 Last updated: 2017-12-04
Keklikoglou, I., Hosaka, K., Bender, C., Bott, A., Koerner, C., Mitra, D., . . . Wiemann, S. (2015). MicroRNA-206 functions as a pleiotropic modulator of cell proliferation, invasion and lymphangiogenesis in pancreatic adenocarcinoma by targeting ANXA2 and KRAS genes. Oncogene, 34(37), 4867-4878
Open this publication in new window or tab >>MicroRNA-206 functions as a pleiotropic modulator of cell proliferation, invasion and lymphangiogenesis in pancreatic adenocarcinoma by targeting ANXA2 and KRAS genes
Show others...
2015 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 34, no 37, p. 4867-4878Article in journal (Refereed) Published
Abstract [en]

Recent advances in cancer biology have emerged important roles for microRNAs (miRNAs) in regulating tumor responses. However, their function in mediating intercellular communication within the tumor microenvironment is thus far poorly explored. Here, we found miR-206 to be abrogated in human pancreatic ductal adenocarcinoma (PDAC) specimens and cell lines. We show that miR-206 directly targets the oncogenes KRAS and annexin a2 (ANXA2), thereby acting as tumor suppressor in PDAC cells by blocking cell cycle progression, cell proliferation, migration and invasion. Importantly, we identified miR-206 as a negative regulator of oncogenic KRAS-induced nuclear factor-kappa B transcriptional activity, resulting in a concomitant reduction of the expression and secretion of pro-angiogenic and pro-inflammatory factors including the cytokine interleukin-8, the chemokines (C-X-C motif) ligand 1 and (C-C motif) ligand 2, and the granulocyte macrophage colony-stimulating factor. We further show that miR-206 abrogates the expression and secretion of the potent pro-lymphangiogenic factor vascular endothelial growth factor C in pancreatic cancer cells through an NF-kappa B-independent mechanism. By using in vitro and in vivo approaches, we reveal that re-expression of miR-206 in PDAC cells is sufficient to inhibit tumor blood and lymphatic vessel formation, thus leading to a significant delay of tumor growth and progression. Taken together, our study sheds light onto the role of miR-206 as a pleiotropic modulator of different hallmarks of cancer, and as such raising the intriguing possibility that miR-206 may be an attractive candidate for miRNA-based anticancer therapies.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2015
National Category
Basic Medicine
Identifiers
urn:nbn:se:liu:diva-121743 (URN)10.1038/onc.2014.408 (DOI)000361050000007 ()25500542 (PubMedID)
Note

Funding Agencies|German Federal Ministry of Education and Research (NGFN grant) [01GS0816]; Deutsche Forschungsgemeinschaft (DIP project) [WI3499/1-1]

Available from: 2015-10-06 Created: 2015-10-05 Last updated: 2018-01-11
Organisations

Search in DiVA

Show all publications