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Sipkins, Dorothy Ann

Positions:

Associate Professor of Medicine

Medicine, Hematologic Malignancies and Cellular Therapy
School of Medicine

Associate Research Professor in Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Regeneration Next Initiative

Regeneration Next Initiative
School of Medicine

Education:

M.D. 1999

M.D. — Stanford University School of Medicine

Ph.D. 1999

Ph.D. — Stanford University School of Medicine

Internship and Residency, Internal Medicine

Massachusetts General Hospital

Hematology-Oncology Fellowship, Hematology Oncology

Dana Farber Cancer Institute

News:

Grants:

Duke CTSA (KL2)

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
May 02, 2018
End Date
April 30, 2023

Duke CTSA (TL1)

Administered By
Institutes and Centers
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
May 02, 2018
End Date
April 30, 2023

Defining the Rules of Breast Cancer Cell Traffic Through Bone

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
January 09, 2017
End Date
December 31, 2021

Transfusion Medicine and Hematology

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Participating Faculty Member
Start Date
July 01, 1975
End Date
June 30, 2021

Transfusion Medicine and Hematology

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Participating Faculty Member
Start Date
July 01, 1975
End Date
June 30, 2021

Targeting Dormant Breast Cancer Micrometastases to Prevent Disease Relapse

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Role
Principal Investigator
Start Date
January 01, 2019
End Date
December 31, 2020

Targeting sphingosine kinase 2 for the treatment of multiple myeloma

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
August 03, 2015
End Date
July 31, 2020

Targeting sphingosine kinase 2 for the treatment of multiple myeloma

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
August 03, 2015
End Date
July 31, 2020

Role of Osteopontin in Induction of Leukemia Dormancy in the Bone Marrow

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Role
Principal Investigator
Start Date
April 01, 2014
End Date
June 30, 2018

GMI-2

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Role
Principal Investigator
Start Date
October 01, 2016
End Date
September 30, 2017

Investigation of PI3Kdelta inhibitor activity in mouse xenograft models of pre-B acute lymphoblastic leukemia ALL

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Role
Principal Investigator
Start Date
April 27, 2016
End Date
April 26, 2017

Investigation of CX-01 in InVitro Pre-Clinical Models of Leukemia

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Role
Principal Investigator
Start Date
June 09, 2015
End Date
June 30, 2016

Regulation of Leukemia Cell Dormancy by the Bone Marrow Microenvironment

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Role
Principal Investigator
Start Date
June 01, 2014
End Date
May 31, 2015
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Publications:

Leukaemia hijacks a neural mechanism to invade the central nervous system.

Acute lymphoblastic leukaemia (ALL) has a marked propensity to metastasize to the central nervous system (CNS). In contrast to brain metastases from solid tumours, metastases of ALL seldom involve the parenchyma but are isolated to the leptomeninges, which is an infrequent site for carcinomatous invasion. Although metastasis to the CNS occurs across all subtypes of ALL, a unifying mechanism for invasion has not yet been determined. Here we show that ALL cells in the circulation are unable to breach the blood-brain barrier in mice; instead, they migrate into the CNS along vessels that pass directly between vertebral or calvarial bone marrow and the subarachnoid space. The basement membrane of these bridging vessels is enriched in laminin, which is known to coordinate pathfinding of neuronal progenitor cells in the CNS. The laminin receptor α6 integrin is expressed in most cases of ALL. We found that α6 integrin-laminin interactions mediated the migration of ALL cells towards the cerebrospinal fluid in vitro. Mice with ALL xenografts were treated with either a PI3Kδ inhibitor, which decreased α6 integrin expression on ALL cells, or specific α6 integrin-neutralizing antibodies and showed significant reductions in ALL transit along bridging vessels, blast counts in the cerebrospinal fluid and CNS disease symptoms despite minimally decreased bone marrow disease burden. Our data suggest that α6 integrin expression, which is common in ALL, allows cells to use neural migratory pathways to invade the CNS.

Authors
Yao, H; Price, TT; Cantelli, G; Ngo, B; Warner, MJ; Olivere, L; Ridge, SM; Jablonski, EM; Therrien, J; Tannheimer, S; McCall, CM; Chenn, A; Sipkins, DA
MLA Citation
Yao, Hisayuki, et al. “Leukaemia hijacks a neural mechanism to invade the central nervous system..” Nature, vol. 560, no. 7716, Aug. 2018, pp. 55–60. Pubmed, doi:10.1038/s41586-018-0342-5.
PMID
30022166
Source
pubmed
Published In
Nature
Volume
560
Issue
7716
Publish Date
2018
Start Page
55
End Page
60
DOI
10.1038/s41586-018-0342-5

Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone.

Breast cancer metastatic relapse can occur years after therapy, indicating that disseminated breast cancer cells (BCCs) have a prolonged dormant phase before becoming proliferative. A major site of disease dissemination and relapse is bone, although the critical signals that allow circulating BCCs to identify bone microvasculature, enter tissue, and tether to the microenvironment are poorly understood. Using real-time in vivo microscopy of bone marrow (BM) in a breast cancer xenograft model, we show that dormant and proliferating BCCs occupy distinct areas, with dormant BCCs predominantly found in E-selectin- and stromal cell-derived factor 1 (SDF-1)-rich perisinusoidal vascular regions. We use highly specific inhibitors of E-selectin and C-X-C chemokine receptor type 4 (CXCR4) (SDF-1 receptor) to demonstrate that E-selectin and SDF-1 orchestrate opposing roles in BCC trafficking. Whereas E-selectin interactions are critical for allowing BCC entry into the BM, the SDF-1/CXCR4 interaction anchors BCCs to the microenvironment, and its inhibition induces mobilization of dormant micrometastases into circulation. Homing studies with primary BCCs also demonstrate that E-selectin regulates their entry into bone through the sinusoidal niche, and immunohistochemical staining of patient BMs shows dormant micrometastatic disease adjacent to SDF-1(+) vasculature. These findings shed light on how BCCs traffic within the host, and suggest that simultaneous blockade of CXCR4 and E-selectin in patients could molecularly excise dormant micrometastases from the protective BM environment, preventing their emergence as relapsed disease.

Authors
Price, TT; Burness, ML; Sivan, A; Warner, MJ; Cheng, R; Lee, CH; Olivere, L; Comatas, K; Magnani, J; Kim Lyerly, H; Cheng, Q; McCall, CM; Sipkins, DA
MLA Citation
Price, Trevor T., et al. “Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone..” Sci Transl Med, vol. 8, no. 340, May 2016. Pubmed, doi:10.1126/scitranslmed.aad4059.
PMID
27225183
Source
pubmed
Published In
Sci Transl Med
Volume
8
Issue
340
Publish Date
2016
Start Page
340ra73
DOI
10.1126/scitranslmed.aad4059

Abstract 3212: Metastatic breast cancer cell communication within a pro-dormancy bone marrow niche

Authors
Price, TT; Lee, CH; Cheng, Q; Lyerly, HK; Fogler, WE; Magnani, JL; Sipkins, DA
MLA Citation
Price, Trevor T., et al. “Abstract 3212: Metastatic breast cancer cell communication within a pro-dormancy bone marrow niche.” Tumor Biology, American Association for Cancer Research, 2015. Crossref, doi:10.1158/1538-7445.am2015-3212.
Source
crossref
Published In
Tumor Biology
Publish Date
2015
DOI
10.1158/1538-7445.am2015-3212

Abstract 4831: Breast cancer cells metastasize to bone through E-selectin+ vascular gateways

Authors
Price, T; Burness, M; Sivan, A; Cheng, R; Magnani, JL; Sipkins, DA
MLA Citation
Price, Trevor, et al. “Abstract 4831: Breast cancer cells metastasize to bone through E-selectin+ vascular gateways.” Tumor Biology, American Association for Cancer Research, 2014. Crossref, doi:10.1158/1538-7445.am2014-4831.
Source
crossref
Published In
Tumor Biology
Publish Date
2014
DOI
10.1158/1538-7445.am2014-4831

Rewiring the niche: sympathetic neuropathy drives malignant niche transformation.

In recent years, it has become increasingly evident that hematological malignancies can alter their microenvironment, but the therapeutic implications of these changes and potential targets have not been well characterized. Recent findings now describe how sympathetic neuropathy can drive malignant transformation of the hematopoietic stem cell niche in hematopoietic malignancies.

Authors
Price, T; Sipkins, DA
MLA Citation
Price, Trevor, and Dorothy A. Sipkins. “Rewiring the niche: sympathetic neuropathy drives malignant niche transformation..” Cell Stem Cell, vol. 15, no. 3, Sept. 2014, pp. 261–62. Pubmed, doi:10.1016/j.stem.2014.08.012.
PMID
25192459
Source
pubmed
Published In
Cell Stem Cell
Volume
15
Issue
3
Publish Date
2014
Start Page
261
End Page
262
DOI
10.1016/j.stem.2014.08.012

The bone marrow microenvironment and its impact in acute and chronic B cell malignancies

© 2012 Springer-Verlag London. All rights are reserved. The bone marrow (BM) hosts normal hematopoiesis by providing the cellular and molecular environment necessary for hematopoietic stem cell maintenance, expansion, and differentiation into the various hematopoietic lineages. This highly organized factory requires cross talk between hematopoietic and stromal elements in distinct microanatomical sites (niches), promoting the expansion of normal hematopoietic elements and the deletion of defective and potentially harmful cells [1]. The neoplastic cells from patients with lymphoid malignancies take advantage of the BM microenvironment by parasitizing niches that normally are restricted to hematopoietic progenitors [2]. Interactions with the marrow microenvironment contribute to malignant B cell growth and drug resistance, leading to a gradual replacement of normal hematopoiesis. In lymphoid malignancies, the BM also is a common site for residual disease and relapses after conventional therapies [3]. Therefore, there is growing interest in understanding the biology of the BM microenvironment. Over the last two decades, there has been substantial progress in identifying key cellular and molecular players in cross talk between malignant lymphocytes and the marrow microenvironment. In this chapter, we will highlight established pathways and current therapeutic approaches to target the microenvironment in acute and chronic B cell malignancies.

Authors
Burger, JA; Sipkins, DA
MLA Citation
Burger, J. A., and D. A. Sipkins. “The bone marrow microenvironment and its impact in acute and chronic B cell malignancies.” Bone Marrow Lymphoid Infiltrates: Diagnosis and Clinical Impact, 2013, pp. 35–45. Scopus, doi:10.1007/978-1-4471-4174-7_3.
Source
scopus
Publish Date
2013
Start Page
35
End Page
45
DOI
10.1007/978-1-4471-4174-7_3

Stem cell factor expression in B cell malignancies is influenced by the niche.

Our group has previously demonstrated that expression of the cytokine stem cell factor (SCF) by leukemic blasts is a frequent finding in pre-B acute lymphoblastic leukemia (ALL). Whether SCF expression is a feature of other B cell malignancies and whether cross-talk from the local microenvironment modulates malignant cell SCF production are, however, unknown. Here we show using immunohistochemistry that SCF is expressed by a wide variety of indolent and aggressive B cell malignancies involving the bone marrow (BM) or lymph nodes (LNs). In diseases such as follicular lymphoma (FL), however, where lymphoma cells uniquely associate with the BM endosteal niche, BM lymphoma does not express SCF, while LN involvement is SCF positive. In contrast, cases of FL with high-grade transformation in the BM are SCF positive. These data suggest that lymphoma cell interaction with the endosteal niche inhibits SCF production, and that FL cells become independent of this microenvironment effect following transformation.

Authors
Fox, MF; Pontier, A; Gurbuxani, S; Sipkins, DA
MLA Citation
Fox, Matthew F., et al. “Stem cell factor expression in B cell malignancies is influenced by the niche..” Leuk Lymphoma, vol. 54, no. 10, Oct. 2013, pp. 2274–80. Pubmed, doi:10.3109/10428194.2013.777067.
PMID
23418895
Source
pubmed
Published In
Leuk Lymphoma
Volume
54
Issue
10
Publish Date
2013
Start Page
2274
End Page
2280
DOI
10.3109/10428194.2013.777067

Adhesion to osteopontin in the bone marrow niche regulates lymphoblastic leukemia cell dormancy.

Malignant cells may evade death from cytotoxic agents if they are in a dormant state. The host microenvironment plays important roles in cancer progression, but how niches might control cancer cell dormancy is little understood. Here we show that osteopontin (OPN), an extracellular matrix molecule secreted by osteoblasts, can function to anchor leukemic blasts in anatomic locations supporting tumor dormancy. We demonstrate that acute lymphoblastic leukemia (ALL) cells specifically adhere to OPN in vitro and secrete OPN when localized to the endosteal niche in vivo. Using intravital microscopy to perform imaging studies of the calvarial bone marrow (BM) of xenografted mice, we show that OPN is highly expressed adjacent to dormant tumor cells within the marrow. Inhibition of the OPN-signaling axis significantly increases the leukemic cell Ki-67 proliferative index and leads to a twofold increase in tumor burden in treated mice. Moreover, using cell-cycle-dependent Ara-C chemotherapy to produce minimal residual disease (MRD) in leukemic mice, we show that OPN neutralization synergizes with Ara-C to reduce detectable BM MRD. Taken together, these data suggest that ALL interacts with extracellular OPN within the malignant BM, and that this interaction induces cell cycle exit in leukemic blasts, protecting them from cytotoxic chemotherapy.

Authors
Boyerinas, B; Zafrir, M; Yesilkanal, AE; Price, TT; Hyjek, EM; Sipkins, DA
MLA Citation
Boyerinas, Benjamin, et al. “Adhesion to osteopontin in the bone marrow niche regulates lymphoblastic leukemia cell dormancy..” Blood, vol. 121, no. 24, June 2013, pp. 4821–31. Pubmed, doi:10.1182/blood-2012-12-475483.
PMID
23589674
Source
pubmed
Published In
Blood
Volume
121
Issue
24
Publish Date
2013
Start Page
4821
End Page
4831
DOI
10.1182/blood-2012-12-475483

Polycythemia Vera and Chronic Idiopathic Myelofibrosis CD34+Cells Preferentially Traffic to Splenic Niches

Authors
Horton, B; Zafrir, M; Wales, P; Pontier, A; Tefferi, A; Sipkins, DA
MLA Citation
Horton, Brendan, et al. “Polycythemia Vera and Chronic Idiopathic Myelofibrosis CD34+Cells Preferentially Traffic to Splenic Niches.” Blood, vol. 120, no. 21, AMER SOC HEMATOLOGY, 2012.
Source
wos
Published In
Blood
Volume
120
Issue
21
Publish Date
2012

A Phase II Prospective Feasibility Study of Clofarabine Cytoreduction Prior to Allogeneic Hematopoietic Cell Transplantation (HCT) for Patients with Relapsed or Refractory Acute Leukemias and Advanced Myelodysplastic Syndromes

Authors
Agarwal, R; Locke, FL; Kunnavakkam, R; van Besien, K; Larson, RA; Odenike, O; Godley, L; Liu, H; Le Beau, MM; Gurbuxani, S; Thirman, MJ; Sipkins, DA; White, C; Artz, A; Stock, W
MLA Citation
Agarwal, Rajiv, et al. “A Phase II Prospective Feasibility Study of Clofarabine Cytoreduction Prior to Allogeneic Hematopoietic Cell Transplantation (HCT) for Patients with Relapsed or Refractory Acute Leukemias and Advanced Myelodysplastic Syndromes.” Blood, vol. 118, no. 21, AMER SOC HEMATOLOGY, 2011, pp. 231–32.
Source
wos
Published In
Blood
Volume
118
Issue
21
Publish Date
2011
Start Page
231
End Page
232

Hijacking the Niche: The Role of Stromal Osteopontin in the Induction of Leukemic Dormancy within the Bone Marrow Microenvironment

Authors
Boyerinas, B; Yesilkanal, AE; Pontier, A; Sipkins, DA
MLA Citation
Boyerinas, Benjamin, et al. “Hijacking the Niche: The Role of Stromal Osteopontin in the Induction of Leukemic Dormancy within the Bone Marrow Microenvironment.” Blood, vol. 118, no. 21, AMER SOC HEMATOLOGY, 2011, pp. 342–43.
Source
wos
Published In
Blood
Volume
118
Issue
21
Publish Date
2011
Start Page
342
End Page
343

HSPCs in the balance: The vascular niche.

Authors
Boyerinas, B; Sipkins, DA
MLA Citation
Boyerinas, Benjamin, and Dorothy A. Sipkins. “HSPCs in the balance: The vascular niche..” Cell Stem Cell, vol. 7, no. 6, Dec. 2010, pp. 645–46. Pubmed, doi:10.1016/j.stem.2010.11.021.
PMID
21112557
Source
pubmed
Published In
Cell Stem Cell
Volume
7
Issue
6
Publish Date
2010
Start Page
645
End Page
646
DOI
10.1016/j.stem.2010.11.021

The stem cell niche in health and malignancy.

Somatic stem cells play a well-defined and important role in tissue renewal. Their malignant counterparts, cancer stem cells, are thought to be responsible for tumor initiation and possibly chemotherapy resistance, although controversy remains regarding both the origin and characterization of these cells. Both somatic and cancer stem cells appear to occupy specialized microenvironments in many organs. These niches are important for both maintenance of quiescence and control of cellular survival and proliferation. Targeting cancer stem cells and their microenvironments may provide new therapies to eradicate tumors. The efficacy of several drugs in current use is mediated at least in part via effects on the microenvironment, and new drugs that target the niche are currently in clinical trials.

Authors
Burness, ML; Sipkins, DA
MLA Citation
Burness, Monika L., and Dorothy A. Sipkins. “The stem cell niche in health and malignancy..” Semin Cancer Biol, vol. 20, no. 2, Apr. 2010, pp. 107–15. Pubmed, doi:10.1016/j.semcancer.2010.05.006.
PMID
20510363
Source
pubmed
Published In
Semin Cancer Biol
Volume
20
Issue
2
Publish Date
2010
Start Page
107
End Page
115
DOI
10.1016/j.semcancer.2010.05.006

Rendering the leukemia cell susceptible to attack.

Authors
Sipkins, DA
MLA Citation
Sipkins, Dorothy A. “Rendering the leukemia cell susceptible to attack..” N Engl J Med, vol. 361, no. 13, Sept. 2009, pp. 1307–09. Pubmed, doi:10.1056/NEJMcibr0904291.
PMID
19776414
Source
pubmed
Published In
The New England Journal of Medicine
Volume
361
Issue
13
Publish Date
2009
Start Page
1307
End Page
1309
DOI
10.1056/NEJMcibr0904291

Leukemic cells create bone marrow niches that disrupt the behavior of normal hematopoietic progenitor cells.

The host tissue microenvironment influences malignant cell proliferation and metastasis, but little is known about how tumor-induced changes in the microenvironment affect benign cellular ecosystems. Applying dynamic in vivo imaging to a mouse model, we show that leukemic cell growth disrupts normal hematopoietic progenitor cell (HPC) bone marrow niches and creates abnormal microenvironments that sequester transplanted human CD34+ (HPC-enriched) cells. CD34+ cells in leukemic mice declined in number over time and failed to mobilize into the peripheral circulation in response to cytokine stimulation. Neutralization of stem cell factor (SCF) secreted by leukemic cells inhibited CD34+ cell migration into malignant niches, normalized CD34+ cell numbers, and restored CD34+ cell mobilization in leukemic mice. These data suggest that the tumor microenvironment causes HPC dysfunction by usurping normal HPC niches and that therapeutic inhibition of HPC interaction with tumor niches may help maintain normal progenitor cell function in the setting of malignancy.

Authors
Colmone, A; Amorim, M; Pontier, AL; Wang, S; Jablonski, E; Sipkins, DA
MLA Citation
Colmone, Angela, et al. “Leukemic cells create bone marrow niches that disrupt the behavior of normal hematopoietic progenitor cells..” Science, vol. 322, no. 5909, Dec. 2008, pp. 1861–65. Pubmed, doi:10.1126/science.1164390.
PMID
19095944
Source
pubmed
Published In
Science
Volume
322
Issue
5909
Publish Date
2008
Start Page
1861
End Page
1865
DOI
10.1126/science.1164390

MALIGNANT GROWTH IN THE BONE MARROW CREATES ABNORMAL HEMATOPOIETIC PROGENITOR CELL NICHES

Authors
Colmone, A; Amorim, M; Pontier, A; Wang, S; Jablonski, E; Sipkins, DA
MLA Citation
Colmone, Angela, et al. “MALIGNANT GROWTH IN THE BONE MARROW CREATES ABNORMAL HEMATOPOIETIC PROGENITOR CELL NICHES.” Anticancer Research, vol. 28, no. 5C, INT INST ANTICANCER RESEARCH, Sept. 2008, pp. 3555–3555.
Source
wos
Published In
Anticancer Research
Volume
28
Issue
5C
Publish Date
2008
Start Page
3555
End Page
3555

Beyond angiogenesis: the role of endothelium in the bone marrow vascular niche.

Specific tissue microenvironments, or niches, are critical for homing and maintenance of both stem cells and tumor cells in vivo. Little is known, however, about the molecular interactions between individual cells within these microenvironments. Recent studies that describe a newly identified hematopoietic stem and tumor cell vascular niche in the bone marrow (BM) suggest a critical role for vascular endothelial cell signaling and raise the possibility that bidirectional interactions of these cells with the vasculature regulate the niche dynamically. The mechanisms that govern hematopoietic stem cell (HSC)/tumor cell cross-talk with endothelial cells provide a promising new direction for future studies. Here we review recent advances that open new avenues of study in this field.

Authors
Colmone, A; Sipkins, DA
MLA Citation
Colmone, Angela, and Dorothy A. Sipkins. “Beyond angiogenesis: the role of endothelium in the bone marrow vascular niche..” Transl Res, vol. 151, no. 1, 2008, pp. 1–9. Pubmed, doi:10.1016/j.trsl.2007.09.003.
PMID
18061122
Source
pubmed
Published In
Translational Research : the Journal of Laboratory and Clinical Medicine
Volume
151
Issue
1
Publish Date
2008
Start Page
1
End Page
9
DOI
10.1016/j.trsl.2007.09.003

Chemotherapy and the bone marrow stroma.

Authors
Sipkins, DA
MLA Citation
Sipkins, Dorothy A. “Chemotherapy and the bone marrow stroma..” Leuk Lymphoma, vol. 49, no. 1, Jan. 2008, pp. 17–18. Pubmed, doi:10.1080/10428190701784748.
PMID
18203006
Source
pubmed
Published In
Leuk Lymphoma
Volume
49
Issue
1
Publish Date
2008
Start Page
17
End Page
18
DOI
10.1080/10428190701784748

Dynamic in vivo imaging reveals that leukemia-induced changes in the bone marrow microenvironment alter mechanisms of metastasis

Authors
Colmone, A; Krishmamoorthy, V; Sipkins, DA
MLA Citation
Colmone, Angela, et al. “Dynamic in vivo imaging reveals that leukemia-induced changes in the bone marrow microenvironment alter mechanisms of metastasis.” Blood, vol. 110, no. 11, AMER SOC HEMATOLOGY, 2007, pp. 825A-825A.
Source
wos
Published In
Blood
Volume
110
Issue
11
Publish Date
2007
Start Page
825A
End Page
825A

Real-time detection of circulating apoptotic cells by in vivo flow cytometry.

Authors
Wei, X; Sipkins, DA; Pitsillides, CM; Novak, J; Georgakoudi, I; Lin, CP
MLA Citation
Wei, Xunbin, et al. “Real-time detection of circulating apoptotic cells by in vivo flow cytometry..” Mol Imaging, vol. 4, no. 4, Oct. 2005, pp. 415–16.
PMID
16285902
Source
pubmed
Published In
Molecular Imaging
Volume
4
Issue
4
Publish Date
2005
Start Page
415
End Page
416

In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment.

The organization of cellular niches is known to have a key role in regulating normal stem cell differentiation and regeneration, but relatively little is known about the architecture of microenvironments that support malignant metastasis. Using dynamic in vivo confocal imaging, here we show that murine bone marrow contains unique anatomic regions defined by specialized endothelium. This vasculature expresses the adhesion molecule E-selectin and the chemoattractant stromal-cell-derived factor 1 (SDF-1) in discrete, discontinuous areas that influence the homing of a variety of tumour cell lines. Disruption of the interactions between SDF-1 and its receptor CXCR4 inhibits the homing of Nalm-6 cells (an acute lymphoblastic leukaemia cell line) to these vessels. Further studies revealed that circulating leukaemic cells can engraft around these vessels, suggesting that this molecularly distinct vasculature demarcates a microenvironment for early metastatic tumour spread in bone marrow. Finally, purified haematopoietic stem/progenitor cells and lymphocytes also localize to the same microdomains, indicating that this vasculature might also function in benign states to demarcate specific portals for the entry of cells into the marrow space. Specialized vascular structures therefore appear to delineate a microenvironment with unique physiology that can be exploited by circulating malignant cells.

Authors
Sipkins, DA; Wei, X; Wu, JW; Runnels, JM; Côté, D; Means, TK; Luster, AD; Scadden, DT; Lin, CP
MLA Citation
Sipkins, Dorothy A., et al. “In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment..” Nature, vol. 435, no. 7044, June 2005, pp. 969–73. Pubmed, doi:10.1038/nature03703.
PMID
15959517
Source
pubmed
Published In
Nature
Volume
435
Issue
7044
Publish Date
2005
Start Page
969
End Page
973
DOI
10.1038/nature03703

Specialized bone marrow endothelium defines microdomains for tumor and stem cell engraftment.

Authors
Sipkins, DA; Wei, XB; Wu, JW; Means, TK; Luster, AD; Lin, CP; Scadden, DT
MLA Citation
Sipkins, D. A., et al. “Specialized bone marrow endothelium defines microdomains for tumor and stem cell engraftment..” Blood, vol. 104, no. 11, AMER SOC HEMATOLOGY, 2004, pp. 191A-191A.
Source
wos
Published In
Blood
Volume
104
Issue
11
Publish Date
2004
Start Page
191A
End Page
191A

ICAM-1 expression in autoimmune encephalitis visualized using magnetic resonance imaging.

The expression of leukocyte adhesion molecules in the intact brains of mice with experimental autoimmune encephalitis (EAE) was visualized by Magnetic Resonance Imaging (MRI) through the use of a new, target-specific MR contrast agent. Antibody-conjugated paramagnetic liposomes (ACPLs) were designed to achieve in vivo targeting of molecules expressed on vascular endothelium, while providing sufficient signal enhancement at these sites for detection by MRI. ACPLs targeted to intercellular adhesion molecule-1 (ICAM-1), an endothelial leukocyte receptor upregulated on cerebral microvasculature during EAE, were administered to diseased mice. Fluorescence microscopy confirmed that fluorescently-tagged ACPLs were localized to central nervous system (CNS) microvasculature in a pattern consistent with ICAM-1 upregulation described immunohistochemically. High resolution MRI of mouse brains ex vivo demonstrated that ACPL binding conferred significant enhancement of signal intensity (SI) as compared to control images. These results suggest that ACPLs can be used as MRI contrast agents to visualize specific molecules expressed on vascular endothelium during disease.

Authors
Sipkins, DA; Gijbels, K; Tropper, FD; Bednarski, M; Li, KC; Steinman, L
MLA Citation
Sipkins, D. A., et al. “ICAM-1 expression in autoimmune encephalitis visualized using magnetic resonance imaging..” J Neuroimmunol, vol. 104, no. 1, Apr. 2000, pp. 1–9.
PMID
10683508
Source
pubmed
Published In
Journal of Neuroimmunology
Volume
104
Issue
1
Publish Date
2000
Start Page
1
End Page
9

Detection of tumor angiogenesis in vivo by alphaVbeta3-targeted magnetic resonance imaging.

Angiogenesis, the formation of new blood vessels, is a requirement for malignant tumor growth and metastasis. In the absence of angiogenesis, local tumor expansion is suppressed at a few millimeters and cells lack routes for distant hematogenous spread. Clinical studies have demonstrated that the degree of angiogenesis is correlated with the malignant potential of several cancers, including breast cancer and malignant melanoma. Moreover, the expression of a specific angiogenesis marker, the endothelial integrin alphaVbeta3, has been shown to correlate with tumor grade. However, studies of tumor angiogenesis such as these have generally relied on invasive procedures, adequate tissue sampling and meticulous estimation of histologic microvessel density. In the present report, we describe a novel approach to detecting angiogenesis in vivo using magnetic resonance imaging (MRI) and a paramagnetic contrast agent targeted to endothelial alphaVbeta3 via the LM609 monoclonal antibody. This approach provided enhanced and detailed imaging of rabbit carcinomas by directly targeting paramagnetic agents to the angiogenic vasculature. In addition, angiogenic 'hot spots' not seen by standard MRI were detected. Our strategy for MR imaging of alphaVbeta3 thus represents a non-invasive means to assess the growth and malignant phenotype of tumors.

Authors
Sipkins, DA; Cheresh, DA; Kazemi, MR; Nevin, LM; Bednarski, MD; Li, KC
MLA Citation
Sipkins, D. A., et al. “Detection of tumor angiogenesis in vivo by alphaVbeta3-targeted magnetic resonance imaging..” Nat Med, vol. 4, no. 5, May 1998, pp. 623–26.
PMID
9585240
Source
pubmed
Published In
Nature Medicine
Volume
4
Issue
5
Publish Date
1998
Start Page
623
End Page
626

ANTIBODY-CONJUGATED PARAMAGNETIC LIPOSOMES - TISSUE-SPECIFIC CONTRAST AGENTS FOR DISEASE PROCESSES

Authors
SIPKINS, DA; GIJBELS, K; TROPPER, FD; STEINMAN, L; BEDNARSKI, MD
MLA Citation
SIPKINS, D. A., et al. “ANTIBODY-CONJUGATED PARAMAGNETIC LIPOSOMES - TISSUE-SPECIFIC CONTRAST AGENTS FOR DISEASE PROCESSES.” Radiology, vol. 197, RADIOLOGICAL SOC NORTH AMER, Nov. 1995, pp. 276–276.
Source
wos
Published In
Radiology
Volume
197
Publish Date
1995
Start Page
276
End Page
276

MR-IMAGING OF TUMOR-INDUCED ANGIOGENESIS WITH ANTIBODY-CONJUGATED PARAMAGNETIC LIPOSOMES

Authors
SIPKINS, DA; CHEN, IY; SONG, CK; CHERESH, DA; BEDNARSKI, MD; LI, KC
MLA Citation
SIPKINS, D. A., et al. “MR-IMAGING OF TUMOR-INDUCED ANGIOGENESIS WITH ANTIBODY-CONJUGATED PARAMAGNETIC LIPOSOMES.” Radiology, vol. 197, RADIOLOGICAL SOC NORTH AMER, Nov. 1995, pp. 129–129.
Source
wos
Published In
Radiology
Volume
197
Publish Date
1995
Start Page
129
End Page
129

Paramagnetic polymerized liposomes as new recirculating MR contrast agents.

We describe a well-tolerated blood pool contrast agent with extended recirculatory half-life based on paramagnetic polymerized liposomes (PPLs). PPLs were constructed from a new type of polymerizable lipid molecule that has a derivative of gadopentetate dimeglumine as the hydrophilic head group and diacetylene groups in the hydrophobic acyl chains, which cross-link when irradiated with ultraviolet (UV) light. Biodistribution, blood pool half-life, and MR image enhancement were determined for PPLs composed of 10% of the gadopentetate dimeglumine lipid and 90% of ditricosadiynoyl tricosadiynayl phosphatidylcholine (DAPC) at a dose of 0.015 mmol Gd+3/kg in rats. In T1-weighed MR images (TR/TE = 400/18 msec), an average signal enhancement of 34% in the kidneys and 20% in the liver was observed, which persisted for at least 90 minutes after administration of the PPLs. Biodistribution studies using radiolabeled PPLs confirmed that 80% of the injected dose remained in the blood pool after 2 hours. The half-life of elimination from the blood pool was 19 hours. The preparation was well tolerated in rats and produced similar MR contrast enhancement of the blood pool as produced by other liposome contrast agents. However, the half-life of PPL elimination from the blood pool was prolonged relative to other liposome systems.

Authors
Storrs, RW; Tropper, FD; Li, HY; Song, CK; Sipkins, DA; Kuniyoshi, JK; Bednarski, MD; Strauss, HW; Li, KC
MLA Citation
Storrs, R. W., et al. “Paramagnetic polymerized liposomes as new recirculating MR contrast agents..” J Magn Reson Imaging, vol. 5, no. 6, Nov. 1995, pp. 719–24.
PMID
8748492
Source
pubmed
Published In
Journal of Magnetic Resonance Imaging : Jmri
Volume
5
Issue
6
Publish Date
1995
Start Page
719
End Page
724

Paramagnetic polymerized liposomes: Synthesis, characterization, and applications for magnetic resonance imaging

Liposomes are biocompatible materials that show promise as vehicles for drug delivery, inhibitors of cell adhesion, and carriers for the introduction of genetic material into cells. In this paper, we describe the synthesis and characterization of a new class of polymerized liposome particles (paramagnetic polymerized liposome (PPL), Figure 1) that have lanthanide ion chelates as head groups and that can be easily visualized using magnetic resonance imaging (MRI). The R1 molar relaxivity was found to depend primarily on the linker length (m) and on the surface metal density and only weakly on particle size. PPLs containing 10 mol % of compound 1b (m = 2) and 90 mol % of compound 3 had a R1 = 12.2 mM-1 s-1, while PPLs with 10 mol % compound 1a (m = 1) and 90 mol % of compound 3 had a R1 = 5.7 mM-1 s-1. PPLs with 10 mol % of compound 1a and 90 mol % of compound 4 had a R1 = 8.9 mM-1 s-1, while PPLs with 50 mol % of compound 1a and 50 mol % of compound 4 had a R1 = 4.3 rnM-1 s-1. A biotinylated lipid (compound 2) was also incorporated into the particle without affecting R1 relaxivities for use as a marker for histochemical studies. We have also for the first time used atomic force microscopy (AFM) to investigate the size and nature of these particles in an aqueous environment. We feel that these new materials may prove useful for the in vivo investigation of liposome formulations as vehicles for therapeutic applications and for evaluating tissue pathology with MRI.

Authors
Storrs, RW; Tropper, FD; Li, HY; Song, CK; Kuniyoshi, JK; Sipkins, DA; Li, KCP; Bednarski, MD
MLA Citation
Storrs, R. W., et al. “Paramagnetic polymerized liposomes: Synthesis, characterization, and applications for magnetic resonance imaging.” Journal of the American Chemical Society, vol. 117, no. 28, July 1995.
Source
scopus
Published In
Journal of the American Chemical Society
Volume
117
Issue
28
Publish Date
1995

Paramagnetic Polymerized Liposomes: Synthesis, Characterization, and Applications for Magnetic Resonance Imaging

Liposomes are biocompatible materials that show promise as vehicles for drug delivery, inhibitors of cell adhesion, and carriers for the introduction of genetic material into cells. In this paper, we describe the synthesis and characterization of a new class of polymerized liposome particles (paramagnetic polymerized liposome (PPL), Figure 1) that have lanthanide ion chelates as head groups and that can be easily visualized using magnetic resonance imaging (MRI). The R1 molar relaxivity was found to depend primarily on the linker length (m) and on the surface metal density and only weakly on particle size. PPLs containing 10 mol % of compound 1b (m = 2) and 90 mol % of compound 3 had a R1 = 12.2 mM–1 s–1, while PPLs with 10 mol % compound 1a (m = 1) and 90 mol % of compound 3 had a R1 = 5.7 mM–1 s–1. PPLs with 10 mol % of compound la and 90 mol % of compound 4 had a R1 = 8.9 mM–1 s–1, while PPLs with 50 mol % of compound la and 50 mol % of compound 4 had a R1 = 4.3 mM–1 s–1. A biotinylated lipid (compound 2) was also incorporated into the particle without affecting R1 relaxivities for use as a marker for histochemical studies. We have also for the first time used atomic force microscopy (AFM) to investigate the size and nature of these particles in an aqueous environment. We feel that these new materials may prove useful for the in vivo investigation of liposome formulations as vehicles for therapeutic applications and for evaluating tissue pathology with MRI. © 1995, American Chemical Society. All rights reserved.

Authors
Storrs, RW; Tropper, FD; Li, HY; Song, CK; Kuniyoshi, JK; Sipkins, DA; Li, KCP; Bednarski, MD
MLA Citation
Storrs, R. W., et al. “Paramagnetic Polymerized Liposomes: Synthesis, Characterization, and Applications for Magnetic Resonance Imaging.” Journal of the American Chemical Society, vol. 117, no. 28, Jan. 1995, pp. 7301–06. Scopus, doi:10.1021/ja00133a001.
Source
scopus
Published In
Journal of the American Chemical Society
Volume
117
Issue
28
Publish Date
1995
Start Page
7301
End Page
7306
DOI
10.1021/ja00133a001
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