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1.  Connexin-43 upregulation in micrometastases and tumor vasculature and its role in tumor cell attachment to pulmonary endothelium 
BMC Medicine  2008;6:20.
Background
The modulation of gap junctional communication between tumor cells and between tumor and vascular endothelial cells during tumorigenesis and metastasis is complex. The notion of a role for loss of gap junctional intercellular communication in tumorigenesis and metastasis has been controversial. While some of the stages of tumorigenesis and metastasis, such as uncontrolled cell division and cellular detachment, would necessitate the loss of intercellular junctions, other stages, such as intravasation, endothelial attachment, and vascularization, likely require increased cell-cell contact. We hypothesized that, in this multi-stage scheme, connexin-43 is centrally involved as a cell adhesion molecule mediating metastatic tumor attachment to the pulmonary endothelium.
Methods
Tumor cell attachment to pulmonary vasculature, tumor growth, and connexin-43 expression was studied in metastatic lung tumor sections obtained after tail-vein injection into nude mice of syngeneic breast cancer cell lines, overexpressing wild type connexin-43 or dominant-negatively mutated connexin-43 proteins. High-resolution immunofluorescence microscopy and Western blot analysis was performed using a connexin-43 monoclonal antibody. Calcein Orange Red AM dye transfer by fluorescence imaging was used to evaluate the gap junction function.
Results
Adhesion of breast cancer cells to the pulmonary endothelium increased with cancer cells overexpressing connexin-43 and markedly decreased with cells expressing dominant-negative connexin-43. Upregulation of connexin-43 was observed in tumor cell-endothelial cell contact areas in vitro and in vivo, and in areas of intratumor blood vessels and in micrometastatic foci.
Conclusion
Connexin-43 facilitates metastatic 'homing' by increasing adhesion of cancer cells to the lung endothelial cells. The marked upregulation of connexin-43 in tumor cell-endothelial cell contact areas, whether in preexisting 'homing' vessels or in newly formed tumor vessels, suggests that connexin-43 can serve as a potential marker of micrometastases and tumor vasculature and that it may play a role in the early incorporation of endothelial cells into small tumors as seeds for vasculogenesis.
doi:10.1186/1741-7015-6-20
PMCID: PMC2492868  PMID: 18647409
2.  Phase Contrast MRI is an Early Marker of Micrometastatic Breast Cancer Development in the Rat Brain 
Nmr in Biomedicine  2011;25(5):726-736.
The early growth of micrometastatic breast cancer in the brain often occurs through vessel co-option and is independent of angiogenesis. Remodeling of the existing vasculature is an important step in the evolution of co-opting micrometastases into angiogenesis-dependent solid tumor masses. The purpose of this study was to determine if phase contrast MRI, an intrinsic source of contrast exquisitely sensitive to the magnetic susceptibility properties of deoxygenated hemoglobin, could detect vascular changes occurring independent of angiogenesis in a rat model of breast cancer metastases to the brain. Twelve nude rats were administered with 106 MDA-MB-231BRL “brain seeking” breast cancer cells through intracardiac injection. Serial, multiparametric MRI of the brain was performed weekly until metastatic disease was detected. The results demonstrate that images of the signal phase were more sensitive to metastatic brain lesions (area under receiver operating characteristic curve, AUC = 0.97) compared to T2* gradient echo magnitude images, (AUC = 0.73). The difference between the two techniques was likely the result of the confounding effects of edema on the magnitude signal. A region of interest analysis revealed that vascular abnormalities detected with phase contrast MRI preceded tumor permeability as measured with contrast-enhanced MRI by 1 to 2 weeks. Tumor size was correlated with permeability (R2 = 0.23, p < 0.01), but phase contrast was independent of tumor size (R2 = 0.03). Histopathological analysis demonstrated that capillary endothelial cells coopted by tumor cells were significantly enlarged, but less dense, compared to the normal brain vasculature. Whereas co-opted vessels were VEGF-negative, vessels within larger tumor masses were VEGF-positive. In conclusion, phase contrast MRI is believed to be sensitive to vascular remodeling in co-opting brain tumor metastases independent of sprouting angiogenesis and may therefore aid in pre-clinical studies of angiogenic-independent tumors or monitoring continued tumor growth following anti-angiogenic therapy.
doi:10.1002/nbm.1786
PMCID: PMC3252479  PMID: 21954124
magnetic resonance imaging; phase contrast; vascular remodeling; brain metastasis; vessel co-option; ferumoxides
3.  Thyroid gland metastasis from small cell lung cancer: an unusual site of metastatic spread 
Journal of Thoracic Disease  2013;5(2):E21-E24.
Metastasis to the thyroid gland is uncommon compared with the frequency of primary thyroid tumors. The primary sites of metastatic thyroid tumors usually include the breast, lung, kidney and stomach. Among lung cancer types metastasizing to the thyroid, adenocarcinomas are the commonest followed by squamous and large cell carcinomas. Small cell lung carcinoma has not been frequently reported to cause thyroid metastatic deposits. Herein, we describe a patient with small cell lung cancer who developed metastatic lesions to the thyroid and brain simultaneously. Thyroid ultrasonography-guided fine-needle aspiration cytology (US-FNAC) and particularlyimmunocytochemistry documented metastasis from primary lung cancer. Clinical, cytopathological and therapeutic aspects of this unusual site of extrathoracic metastatic disease are discussed laying special emphasis on the paramount importance of the immunocytochemistry in distinguishing primary thyroid tumors from thyroid metastasis due to lung cancer.
doi:10.3978/j.issn.2072-1439.2012.06.03
PMCID: PMC3621935  PMID: 23585950
Small cell lung cancer; thyroid; metastasis; fine-needle aspiration cytology (FNAC); immunocytochemistry
4.  Luminal breast cancer metastasis is dependent on estrogen signaling 
Clinical & experimental metastasis  2012;29(5):10.1007/s10585-012-9466-4.
Luminal breast cancer is the most frequently encountered type of human breast cancer and accounts for half of all breast cancer deaths due to metastatic disease. We have developed new in vivo models of disseminated human luminal breast cancer that closely mimic the human disease. From initial lesions in the tibia, locoregional metastases develop predictably along the iliac and retroperitoneal lymph node chains. Tumors cells retain their epithelioid phenotype throughout the process of dissemination. In addition, systemically injected metastatic MCF-7 cells consistently give rise to metastases in the skeleton, floor of mouth, adrenal glands, as well as in the lungs, liver, brain and mammary fat pad. We show that growth of luminal breast cancer metastases is highly dependent on estrogen in a dose-dependent manner and that estrogen withdrawal induces rapid growth arrest of metastatic disease. On the other hand, even though micrometastases at secondary sites remain viable in the absence of estrogen, they are dormant and do not progress to macrometastases. Thus, homing to and seeding of secondary sites do not require estrogen. Moreover, in sharp contrast to basal-like breast cancer metastasis in which transforming growth factor-β signaling plays a key role, luminal breast cancer metastasis is independent of this cytokine. These findings have important implications for the development of targeted anti-metastatic therapy for luminal breast cancer.
doi:10.1007/s10585-012-9466-4
PMCID: PMC3816364  PMID: 22427027
Luminal breast cancer; Metastasis; Estrogen; Transforming growth factor-β
5.  Comparative exome sequencing of metastatic lesions provides insights into the mutational progression of melanoma 
BMC Genomics  2012;13:505.
Background
Metastasis is characterized by spreading of neoplastic cells to an organ other than where they originated and is the predominant cause of death among cancer patients. This holds true for melanoma, whose incidence is increasing more rapidly than any other cancer and once disseminated has few therapeutic options. Here we performed whole exome sequencing of two sets of matched normal and metastatic tumor DNAs.
Results
Using stringent criteria, we evaluated the similarities and differences between the lesions. We find that in both cases, 96% of the single nucleotide variants are shared between the two metastases indicating that clonal populations gave rise to the distant metastases. Analysis of copy number variation patterns of both metastatic sets revealed a trend similar to that seen with our single nucleotide variants. Analysis of pathway enrichment on tumor sets shows commonly mutated pathways enriched between individual sets of metastases and all metastases combined.
Conclusions
These data provide a proof-of-concept suggesting that individual metastases may have sufficient similarity for successful targeting of driver mutations.
doi:10.1186/1471-2164-13-505
PMCID: PMC3500261  PMID: 23006843
6.  Three-Dimensional Characterization of the Vascular Bed in Bone Metastasis of the Rat by Microcomputed Tomography (MicroCT) 
PLoS ONE  2011;6(3):e17336.
Background
Angiogenesis contributes to proliferation and metastatic dissemination of cancer cells. Anatomy of blood vessels in tumors has been characterized with 2D techniques (histology or angiography). They are not fully representative of the trajectories of vessels throughout the tissues and are not adapted to analyze changes occurring inside the bone marrow cavities.
Methodology/Principal Findings
We have characterized the vasculature of bone metastases in 3D at different times of evolution of the disease. Metastases were induced in the femur of Wistar rats by a local injection of Walker 256/B cells. Microfil®, (a silicone-based polymer) was injected at euthanasia in the aorta 12, 19 and 26 days after injection of tumor cells. Undecalcified bones (containing the radio opaque vascular casts) were analyzed by microCT, and a first 3D model was reconstructed. Bones were then decalcified and reanalyzed by microCT; a second model (comprising only the vessels) was obtained and overimposed on the former, thus providing a clear visualization of vessel trajectories in the invaded metaphysic allowing quantitative evaluation of the vascular volume and vessel diameter. Histological analysis of the marrow was possible on the decalcified specimens. Walker 256/B cells induced a marked osteolysis with cortical perforations. The metaphysis of invaded bones became progressively hypervascular. New vessels replaced the major central medullar artery coming from the diaphyseal shaft. They sprouted from the periosteum and extended into the metastatic area. The newly formed vessels were irregular in diameter, tortuous with a disorganized architecture. A quantitative analysis of vascular volume indicated that neoangiogenesis increased with the development of the tumor with the appearance of vessels with a larger diameter.
Conclusion
This new method evidenced the tumor angiogenesis in 3D at different development times of the metastasis growth. Bone and the vascular bed can be identified by a double reconstruction and allowed a quantitative evaluation of angiogenesis upon time.
doi:10.1371/journal.pone.0017336
PMCID: PMC3065464  PMID: 21464932
7.  Metastatic Squamous Cell Carcinoma of the Skin 
Sunlight induced squamous cell carcinoma of the skin is common and produces low incidence of metastases. Non-actinic squamous cell carcinoma, however, possesses a metastatic potential even when well differentiated. A representative case of keratinizing squamous cell carcinoma arising in a lower extremity with development of widespread metastases is discussed. The prognostic factors associated with metastasizing de novo squamous cell carcinoma of the extremity include: site of origin, duration of lesion, degree of differentiation, sex of patient, and size of the primary lesion. Organs prone to metastasis include: regional lymph nodes, liver, lungs, and bone. As skin cancers of this variety metastasize, the clinician must recognize this potential when considering therapeutic strategy.
Images
PMCID: PMC2609730  PMID: 7310907
8.  MAJOR LIVER RESECTION STIMULATES STROMAL RECRUITMENT AND METASTASIS COMPARED TO REPEATED MINOR RESECTION 
The Journal of surgical research  2012;178(1):280-287.
Background
This study examines the effects of types of liver resection on the growth of liver and lung metastasis.
Materials and Methods
Experimental liver metastases were established by spleen injection of the Colon 26 murine adenocarcinoma cell line expressing GFP into transgenic nude mice expressing RFP. Experimental lung metastases were established by tail vein injection with Colon 26-GFP. Three days after cell injection, groups of mice underwent liver resection (35%+35% [repeated minor resection] vs. 70% [major resection]). Metastatic tumor growth was measured by color-coded fluorescence imaging of the GFP-expressing cancer cells and RFP-expressing stroma.
Results
Although major and repeated minor resection removed the same volume of liver parenchyma, the two procedures had very different effects on metastatic tumor growth: major resection, stimulated liver and lung metastatic growth as well as recruitment of host-derived stroma compared to repeated minor resection. Repeated minor resection did not stimulate metastasis or stromal recruitment. There was no significant difference in liver regeneration between the two groups. Host-derived stroma density, which is stimulated by major resection compared to repeated minor resection, may stimulate growth in the liver-metastatic tumor. TGF-β is also preferentially stimulated by major resection and may play a role in stroma and metastasis stimulation.
Conclusions
The results of this study indicate that when liver resection is necessary, repeated minor liver resection is superior to major liver resection, since major resection, in contrast to repeated minor resection, stimulates metastasis, which should be taken into consideration in clinical situations indicating liver resection.
doi:10.1016/j.jss.2012.03.020
PMCID: PMC3396724  PMID: 22487397
Nude mice; liver resection; lung metastasis; liver metastasis; stroma; green fluorescent protein; red fluorescent protein; color-coded imaging
9.  The role of endotoxin/lipopolysaccharide in surgically induced tumour growth in a murine model of metastatic disease 
British Journal of Cancer  1999;81(8):1311-1317.
Surgical removal of a primary tumour is often followed by rapid growth of previously dormant metastases. Endotoxin or lipopolysaccharide, a cell wall constituent of Gram-negative bacteria, is ubiquitously present in air and may be introduced during surgery. BALB/c mice received a tail vein injection of 105 4T1 mouse mammary carcinoma cells. Two weeks later, animals were subjected to surgical trauma or an intraperitoneal injection of endotoxin (10 μg per animal). Five days later, animals which underwent open surgery, laparoscopy with air sufflation or received an endotoxin injection displayed increased lung metastasis compared to anaesthetic controls. These increases in metastatic tumour growth were reflected in increased tumour cell proliferation and decreased apoptosis within lung metastases. Circulating levels of the angiogenic cytokine, vascular endothelial growth factor (VEGF), were also elevated in these groups and correlated with increased plasma levels of endotoxin. Endotoxin treatment for 18 h (>10 ng ml–1) directly up-regulated VEGF production by the 4T1 tumour cells in vitro. Metastatic tumour growth in mice undergoing carbon dioxide laparoscopy, where air is excluded, was similar to anaesthetic controls. These data indicate that endotoxin introduced during surgery is associated with the enhanced growth of metastases following surgical trauma, by altering the critical balances governing cellular growth and angiogenesis. © 1999 Cancer Research Campaign
doi:10.1038/sj.bjc.6694369
PMCID: PMC2362969  PMID: 10604727
endotoxin; lipopolysaccharide; metastasis; murine tumour; surgery
10.  Multiorgan Metastasis of Human HER-2+ Breast Cancer in Rag2−/−;Il2rg−/− Mice and Treatment with PI3K Inhibitor 
PLoS ONE  2012;7(6):e39626.
In vivo studies of the metastatic process are severely hampered by the fact that most human tumor cell lines derived from highly metastatic tumors fail to consistently metastasize in immunodeficient mice like nude mice. We describe a model system based on a highly immunodeficient double knockout mouse, Rag2−/−;Il2rg−/−, which lacks T, B and NK cell activity. In this model human metastatic HER-2+ breast cancer cells displayed their full multiorgan metastatic potential, without the need for selections or additional manipulations of the system. Human HER-2+ breast cancer cell lines MDA-MB-453 and BT-474 injected into Rag2−/−;Il2rg−/− mice faithfully reproduced human cancer dissemination, with multiple metastatic sites that included lungs, bones, brain, liver, ovaries, and others. Multiorgan metastatic spread was obtained both from local tumors, growing orthotopically or subcutaneously, and from cells injected intravenously. The problem of brain recurrencies is acutely felt in HER-2+ breast cancer, because monoclonal antibodies against HER-2 penetrate poorly the blood-brain barrier. We studied whether a novel oral small molecule inhibitor of downstream PI3K, selected for its penetration of the blood-brain barrier, could affect multiorgan metastatic spread in Rag2−/−; Il2rg−/− mice. NVP-BKM120 effectively controlled metastatic growth in multiple organs, and resulted in a significant proportion of mice free from brain and bone metastases. Human HER-2+ human breast cancer cells in Rag2−/−;Il2rg−/− mice faithfully reproduced the multiorgan metastatic pattern observed in patients, thus allowing the investigation of metastatic mechanisms and the preclinical study of novel antimetastatic agents.
doi:10.1371/journal.pone.0039626
PMCID: PMC3380859  PMID: 22737248
11.  Is tail vein injection a relevant breast cancer lung metastasis model? 
Journal of Thoracic Disease  2013;5(4):385-392.
Background
Two most commonly used animal models for studying breast cancer lung metastasis are: lung metastasis after orthotopic implantation of cells into the mammary gland, and lung implantations produced after tail vein (TV) injection of cells. Tail vein injection can produce lung lesions faster, but little has been studied regarding the differences between these tumors, thus, we examined their morphology and gene expression profiles.
Methods
Syngeneic murine mammary adenocarcinoma, 4T1-luc2 cells, were implanted either subcutaneously (Sq), orthotopically (OS), or injected via TV in Balb/c mice. Genome-wide microarray analyses of cultured 4T1 cells, Sq tumor, OS tumor, lung metastases after OS (LMet), and lung tumors after TV (TVt) were performed 10 days after implantation.
Results
Bioluminescence analysis demonstrated different morphology of metastases between LMet and TVt, confirmed by histology. Gene expression profile of cells were significantly different from tumors, OS, Sq, TVt or LMet (10,350 probe sets; FDR≤1%; P<0.0001). Sq tumors were significantly different than OS tumors (700 probe sets; FDR≤15%; P<0.01), and both tumor types (Sq and OS) were significantly different than LMet (1,247 probe sets; >1.5-fold-change; P<0.01), with no significant difference between TVt and LMet.
Conclusions
There were significant differences between the gene profiles of cells in culture and OS versus LMet, but there were no differences between LMet versus TVt. Therefore, the lung tumor generated by TVt can be considered genetically similar to those produced after OS, and thus TVt is a relevant model for breast cancer lung metastasis.
doi:10.3978/j.issn.2072-1439.2013.06.17
PMCID: PMC3755653  PMID: 23991292
Breast cancer; lung metastasis; animal model; microarray; metastasis model
12.  Antagonism of chemokine receptor CXCR3 inhibits osteosarcoma metastasis to lungs 
Metastasis continues to be the leading cause of mortality for patients with cancer. Several years ago, it became clear that chemokines and their receptors could control the tumor progress. CXCR3 has now been identified in many cancers including osteosarcoma and CXCR3 ligands were expressed by lungs that are the primary sites to which this tumor metastasize. This study tested the hypothesis that disruption of the CXCR3/CXCR3 ligands complexes could lead to a decrease in lungs metastasis. The experimental design involved the use of the CXCR3 antagonist, AMG487 and 2 murine models of osteosarcoma lung metastases. After tail vein injection of osteosarcoma cells, mice that were systematically treated with AMG487 according to preventive or curative protocols had a significant reduction in metastatic disease. Treatment of osteosarcoma cells in vitro with AMG487 led to decreased migration, decreased matrix metalloproteinase activity, decreased proliferation/survival and increased caspase-independent death. Taken together, our results support the hypothesis that CXCR3 and their ligands intervene in the initial dissemination of the osteosarcoma cells to the lungs and stimulate the growth and expansion of the metastatic foci in later stages. Moreover, these studies indicate that targeting CXCR3 may specifically inhibit tumor metastasis without adversely affecting antitumoral host response.
doi:10.1002/ijc.24665
PMCID: PMC2772145  PMID: 19544560
chemokine receptors; osteosarcoma; lung metastasis; animal models
13.  Rhodamine-RCA in vivo labeling guided laser capture microdissection of cancer functional angiogenic vessels in a murine squamous cell carcinoma mouse model 
Molecular Cancer  2006;5:5.
Background
Cancer growth, invasion and metastasis are highly related to tumor-associated neovasculature. The presence and progression of endothelial cells in cancer is chaotic, unorganized, and angiogenic vessels are less functional. Therefore, not all markers appearing on the chaotic endothelial cells are accessible if a drug is given through the vascular route. Identifying endothelial cell markers from functional cancer angiogenic vessels will indicate the accessibility and potential efficacy of vascular targeted therapies.
Results
In order to quickly and effectively identify endothelial cell markers on the functional and accessible tumor vessels, we developed a novel technique by which tumor angiogenic vessels are labeled in vivo followed by Laser Capture Microdissection of microscopically isolated endothelial cells for genomic screening. Female C3H mice (N = 5) with established SCCVII tumors were treated with Rhodamine-RCA lectin by tail vein injection, and after fluorescence microscopy showed a successful vasculature staining, LCM was then performed on frozen section tissue using the PixCell II instrument with CapSure HS caps under the Rhodamine filter. By this approach, the fluorescent angiogenic endothelial cells were successfully picked up. As a result, the total RNA concentration increased from an average of 33.4 ng/ul +/- 24.3 (mean +/- S.D.) to 1913.4 ng/ul +/- 164. Relatively pure RNA was retrieved from both endothelial and epithelial cells as indicated by the 260/280 ratios (range 2.22–2.47). RT-PCR and gene electrophoresis successfully detected CD31 and Beta-Actin molecules with minimal Keratin 19 expression, which served as the negative control.
Conclusion
Our present study demonstrates that in vivo Rhodamine RCA angiogenic vessel labeling provided a practical approach to effectively guide functional endothelial cell isolation by laser capture microdissection with fluorescent microscopy, resulting in high quality RNA and pure samples of endothelial cells pooled for detecting genomic expression.
doi:10.1186/1476-4598-5-5
PMCID: PMC1420324  PMID: 16457726
14.  Rap GTPase-mediated adhesion and migration 
Cell Adhesion & Migration  2010;4(3):327-332.
B-cell lymphomas, which arise in lymphoid organs, can spread rapidly via the circulatory system and form solid tumors within multiple organs. Rate-limiting steps in this metastatic process may be the adhesion of lymphoma cells to vascular endothelial cells, their exit from the vasculature and their migration to tissue sites that will support tumor growth. Thus proteins that control B-cell adhesion and migration are likely to be key factors in lymphoma dissemination, and hence potential targets for therapeutic intervention. The Rap GTPases are master regulators of integrin activation, cell motility and the underlying cytoskeletal, adhesion and membrane dynamics. We have recently shown that Rap activation is critical for B-lymphoma cells to undergo transendothelial migration in vitro and in vivo. As a consequence, suppressing Rap activation impairs the ability of intravenously injected B-lymphoma cells to form solid tumors in the liver and other organs. We discuss this work in the context of targeting Rap, its downstream effectors, or other regulators of B-cell adhesion and migration as an approach for limiting the dissemination of B-lymphoma cells and the development of secondary tumors.
doi:10.4161/cam.4.3.11114
PMCID: PMC2958603  PMID: 20212359
B-cell lymphomas; Rap GTPases; extravasation; chemokines; integrins; metastasis
15.  Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs 
Tumor treating fields (TTFields) are low intensity, intermediate frequency, alternating electric fields used to treat cancerous tumors. This novel treatment modality effectively inhibits the growth of solid tumors in vivo and has shown promise in pilot clinical trials in patients with advanced stage solid tumors. TTFields were tested for their potential to inhibit metastatic spread of solid tumors to the lungs in two animal models: (1) Mice injected with malignant melanoma cells (B16F10) into the tail vein, (2) New Zealand White rabbits implanted with VX-2 tumors within the kidney capsule. Mice and rabbits were treated using two-directional TTFields at 100–200 kHz. Animals were either monitored for survival, or sacrificed for pathological and histological analysis of the lungs. The total number of lung surface metastases and the absolute weight of the lungs were both significantly lower in TTFields treated mice then in sham control mice. TTFields treated rabbits survived longer than sham control animals. This extension in survival was found to be due to an inhibition of metastatic spread, seeding or growth in the lungs of TTFields treated rabbits compared to controls. Histologically, extensive peri- and intra-tumoral immune cell infiltration was seen in TTFields treated rabbits only. These results raise the possibility that in addition to their proven inhibitory effect on the growth of solid tumors, TTFields may also have clinical benefit in the prevention of metastatic spread from primary tumors.
doi:10.1007/s10585-009-9262-y
PMCID: PMC2776150  PMID: 19387848
Tumor treating fields; Metastases; Immune response
16.  Molecular Imaging of CXCR4 Receptor Expression in Human Cancer Xenografts with [64Cu]AMD3100-Positron Emission Tomography 
Cancer research  2010;70(10):3935-3944.
The chemokine receptor CXCR4 and its cognate ligand CXCL12 are pivotal for establishing metastases from many tumor types. Thus, CXCR4 may offer a cell surface target for molecular imaging of metastases, assisting diagnosis, staging and therapeutic monitoring. Further, Noninvasive detection of CXCR4 status of a primary tumor may provide an index of the metastatic potential of the lesion. Here, we report the development and evaluation of a positron-emitting analog of the stem cell mobilizing agent plerixafor, [64Cu]AMD3100, to image this receptor in human tumor xenografts preselected for graded expression of CXCR4. This imaging method was also evaluated in a lung metastases derived from human MDA-MB-231 breast cancer cells. Ex vivo biodistribution studies, performed to validate the in vivo imaging data, confirmed the ability of [64Cu]AMD3100 to image CXCR4 expression. Our findings demonstrate the feasibility of noninvasively imaging CXCR4 by positron emission tomography (PET) using a clinically approved agent as a molecular scaffold.
doi:10.1158/0008-5472.CAN-09-4396
PMCID: PMC2874192  PMID: 20460522
Tumor microenvironment; chemokine receptor; metastasis; molecular imaging; brain tumor; breast cancer
17.  Metastatic Dormancy and Progression in Thyroid Cancer: Targeting Cells in the Metastatic Frontier 
Thyroid  2011;21(5):487-492.
Background
Metastatic dormancy, or the ability of cancer cells to survive but not progress in metastatic environments, is now recognized to be a common occurrence in cancer.
Summary
From a clinical perspective, this phenomenon is common in metastatic well-differentiated thyroid cancer, whereby patients often present with distant metastases that remain stable for years after removal of the primary tumor and subsequent treatment. Experimental data suggest that metastases can develop throughout the life of a cancer and that progression in the distant environment depends on the biology of the cancer cells that metastasize as well as that of the various microenvironments they encounter. A firm understanding of how thyroid cancer cell progression is regulated in different metastatic environments is necessary to devise effective therapies targeting progressive metastatic thyroid cancer.
Conclusion
In this review, current models of metastatic progression and factors that regulate late-stage metastatic progression that are particularly relevant for thyroid cancer are discussed.
doi:10.1089/thy.2011.2121
PMCID: PMC3092721  PMID: 21476892
18.  The IGR-CaP1 Xenograft Model Recapitulates Mixed Osteolytic/Blastic Bone Lesions Observed in Metastatic Prostate Cancer12 
Neoplasia (New York, N.Y.)  2012;14(5):376-387.
Bone metastases have a devastating impact on quality of life and bone pain in patients with prostate cancer and decrease survival. Animal models are important tools in investigating the pathogenesis of the disease and in developing treatment strategies for bone metastases, but few animal models recapitulate spontaneous clinical bone metastatic spread. In the present study, IGR-CaP1, a new cell line derived from primary prostate cancer, was stably transduced with a luciferase-expressing viral vector to monitor tumor growth in mice using bioluminescence imaging. The IGR-CaP1 tumors grew when subcutaneously injected or when orthotopically implanted, reconstituted the prostate adenocarcinoma with glandular acini-like structures, and could disseminate to the liver and lung. Bone lesions were detected using bioluminescence imaging after direct intratibial or intracardiac injections. Anatomic bone structure assessed using high-resolution computed tomographic scans showed both lytic and osteoblastic lesions. Technetium Tc 99m methylene diphosphonate micro single-photon emission computed tomography confirmed the mixed nature of the lesions and the intensive bone remodeling. We also identified an expression signature for responsiveness of IGR-CaP1 cells to the bone microenvironment, namely expression of CXCR4, MMP-9, Runx2, osteopontin, osteoprotegerin, ADAMTS14, FGFBP2, and HBB. The IGR-CaP1 cell line is a unique model derived from a primary tumor, which can reconstitute human prostate adenocarcinoma in animals and generate experimental bone metastases, providing a novel means for understanding the mechanisms of bone metastasis progression and allowing preclinical testing of new therapies.
PMCID: PMC3384425  PMID: 22745584
19.  Metastatic potential of B16 melanoma cells after in vitro selection for organ-specific adherence 
The Journal of Cell Biology  1985;101(3):720-724.
Heterogeneous primary tumors contain subpopulations of cells that differ in ability to metastasize to specific host organs. We have used cryostat sections of host organs to select for metastatic variants of B16 melanoma cells with increased adhesion to specific syngeneic tissues. By repeating the selection procedure with lung tissue, a subpopulation of cells was isolated that demonstrated a specific increase in binding to cryostat sections of mouse lung. This altered binding was reflected by a sixfold increase in the frequency of lung metastasis 21 d after tail vein injection of the tumor cells. In contrast, B16 melanoma cells selected on cryostat sections of mouse brain showed no increase in adhesion to brain or lung tissue and the metastatic pattern in vivo was not significantly different compared with the parent cell line. When cells selected for increased adhesion to cryostat sections of lung were further examined in vitro, they showed altered morphology and increased motility but no change in growth rate. These results demonstrate that alterations in the adhesive interactions between metastatic tumor cells and a specific host tissue can directly affect the frequency of metastasis to that tissue in vivo.
PMCID: PMC2113741  PMID: 4030892
20.  Intratracheal Delivery of CX3CL1-Expressing Mesenchymal Stem Cells to Multiple Lung Tumors 
Molecular Medicine  2009;15(9-10):321-327.
The lung is one of the organs to which cancers from solid tumors frequently metastasize. Multiple tumors in the lung are usually treated by systemic chemotherapy because of the lack of efficient methods of targeting antitumor agents to the lung. Although intratracheal administration is an ideal route for targeting multiple lung tumors, antitumor agents are often harmful to the organ or induce inflammation. Mesenchymal stem cells (MSCs), nonhematopoietic stem cells capable of differentiating into various mesoderm-type cells, have a propensity to migrate to and proliferate in tumor tissues after systemic administration. We intratracheally injected MSCs expressing CX3CL1 (MSC/RGDFKN) into the lung of lung tumor–bearing mice with multiple metastases of C26 or Lewis lung carcinoma (LLC). Antitumor effects were evaluated by counting the number of lung metastases and survival. We demonstrated the tropism of mouse MSCs to lung tumor tissues after intratracheal administration of GFP-positive MSCs. Intratracheal injection of MSC/RGDFKN strongly inhibited growth of lung metastases of C26 or LLC, and thus prolonged survival. Intratracheal injection of MSC/RGDFKN did not induce an inflammatory reaction in the lung. These results suggest that MSCs expressing antitumor agents can be delivered intratracheally into multiple lung tumor tissues without causing inflammation.
doi:10.2119/molmed.2009.00059
PMCID: PMC2710294  PMID: 19603106
21.  Characterization of an animal model of aggressive metastatic pheochromocytoma linked to a specific gene signature 
Pheochromocytomas are chromaffin cell-derived neuroendocrine tumors. There is presently no cure for metastatic pheochromocytoma and no reliable way to distinguish malignant from benign tumors before the development of metastases. In order to successfully manage pheochromocytoma, it is necessary to better understand the biological determinants of tumor behavior. For this purpose, we have recently established a mouse model of metastatic pheochromocytoma using tail vein injection of mouse pheochromocytoma (MPC) cells. We optimized this model modifying the number of cells injected, length of trypsin pre-treatment, and incubation temperature and duration for the MPC cells before injection, and by serial passage and re-selection of tumors exhibiting the metastatic phenotype. We evaluated the effect of these modifications on tumor growth using serial in vivo Magnetic Resonance Imaging studies. These results show that number of cells injected, the pre-injection incubation temperature, and duration of trypsin treatment are important factors to produce faster growing, more aggressive tumors that yielded secondary metastatic lesions. Serial harvest, culture and re-selection of metastatic liver lesions produced even more aggressive pheochromocytoma cells that retained their biochemical phenotype. Microarray gene expression comparison and quantitative real-time PCR of these more aggressive cells to the MPC-parental cell line identified genes that may be important for the metastatic process.
doi:10.1007/s10585-009-9236-0
PMCID: PMC3505859  PMID: 19169894
Animal model; Cell line; Pheochromocytoma; Magnetic resonance imaging; Microarray; Quantitative real-time PCR
22.  Differential Roles of Insulin-like Growth Factor Receptor- and Insulin Receptor-mediated Signaling in the Phenotypes of Hepatocellular Carcinoma Cells12 
Neoplasia (New York, N.Y.)  2009;11(9):835-845.
Intrahepatic and extrahepatic metastases are common findings in hepatocellular carcinoma (HCC). Insulin-like growth factor 2 (IGF2) expression is frequently induced in HCC, and serum IGF2 levels correlate with the presence of extrahepatic metastases. Yet, the role of IGF-induced signaling in the dissemination of HCC remains unclear. We have previously observed elevated IGF2 levels in tumors with metastatic potential in an HCC mouse model. Here, we demonstrate that inhibition of IGF2, or its receptor IGF1R, impairs the migration and invasion activities of murine HCC cells. Furthermore, inhibition of IGF1R also impairs the ability of HCC cells to colonize the lungs after introduction into the circulation through the tail vein but does not impair subcutaneous tumor growth. Collectively, these findings suggest that IGF1R-mediated signaling plays a causative role in tumor dissemination but is not required for tumor growth per se. Although previous studies indicate that IGF ligands can signal through IGF1R/insulin receptor (IR) heterodimers, and IR-A homodimers, we demonstrate that the IR is not required for invasion and metastasis by HCC cells. Finally, we identify matrix metalloproteinase 2 as a mediator of the invasive phenotype downstream of IGF1R-induced signaling. Thus, our studies demonstrate the importance of IGF2-induced signaling in the dissemination of HCC cells.
PMCID: PMC2735682  PMID: 19724677
23.  Tumor Metastasis: Molecular Insights and Evolving Paradigms 
Cell  2011;147(2):275-292.
Metastases represent the end-products of a multi-step cell-biological process termed the invasion-metastasis cascade, which involves dissemination of cancer cells to anatomically distant organ sites and their subsequent adaptation to foreign tissue microenvironments. Each of these events is driven by (1) acquisition of genetic and/or epigenetic alterations within tumor cells and (2) co-option of non-neoplastic stromal cells, which together endow incipient metastatic cells with traits needed to generate macroscopic metastases. Recent advances have provided provocative insights regarding these cell-biological and molecular changes, which carry implications concerning the pathogenesis of metastatic progression and the steps of the invasion-metastasis cascade that appear amenable to therapeutic targeting.
doi:10.1016/j.cell.2011.09.024
PMCID: PMC3261217  PMID: 22000009
24.  Hyperinsulinemia enhances c-Myc-mediated mammary tumor development and advances metastatic progression to the lung in a mouse model of type 2 diabetes 
Introduction
Hyperinsulinemia, which is common in early type 2 diabetes (T2D) as a result of the chronically insulin-resistant state, has now been identified as a specific factor which can worsen breast cancer prognosis. In breast cancer, a high rate of mortality persists due to the emergence of pulmonary metastases.
Methods
Using a hyperinsulinemic mouse model (MKR+/+) and the metastatic, c-Myc-transformed mammary carcinoma cell line Mvt1, we investigated how high systemic insulin levels would affect the progression of orthotopically inoculated primary mammary tumors to lung metastases.
Results
We found that orthotopically injected Mvt1 cells gave rise to larger mammary tumors and to a significantly higher mean number of pulmonary macrometastases in hyperinsulinemic mice over a period of six weeks (hyperinsulinemic, 19.4 ± 2.7 vs. control, 4.0 ± 1.3). When Mvt1-mediated mammary tumors were allowed to develop and metastasize for approximately two weeks and were then surgically removed, hyperinsulinemic mice demonstrated a significantly higher number of lung metastases after a four-week period (hyperinsulinemic, 25.1 ± 4.6 vs. control, 7.4 ± 0.42). Similarly, when Mvt1 cells were injected intravenously, hyperinsulinemic mice demonstrated a significantly higher metastatic burden in the lung than controls after a three-week period (hyperinsulinemic, 6.0 ± 1.63 vs. control, 1.5 ± 0.68). Analysis of Mvt1 cells both in vitro and in vivo revealed a significant up-regulation of the transcription factor c-Myc under hyperinsulinemic conditions, suggesting that hyperinsulinemia may promote c-Myc signaling in breast cancer. Furthermore, insulin-lowering therapy using the beta-adrenergic receptor agonist CL-316243 reduced metastatic burden in hyperinsulinemic mice to control levels.
Conclusions
Hyperinsulinemia in a mouse model promotes breast cancer metastasis to the lung. Therapies to reduce insulin levels in hyperinsulinemic patients suffering from breast cancer could lessen the likelihood of metastatic progression.
doi:10.1186/bcr3089
PMCID: PMC3496123  PMID: 22226054
25.  Microenvironmental regulation of epithelial-mesenchymal transitions in cancer 
Cancer research  2012;72(19):4883-4889.
The evolution of the cancer cell into a metastatic entity is the major cause of death in cancer patients. Activation of epithelial to mesenchymal transition (EMT) endows invasive and metastatic properties upon cancer cells that favor successful colonization of distal target organs. The observation that in many cancers distant metastases resemble the epithelial phenotype of primary tumors has led to speculation that the disseminated tumor cells recruited to the target organs undergo mesenchymal to epithelial transition (MET). However, the MET cascade has not been recapitulated in vivo, and the cellular and molecular regulators that promote MET remain unknown. In a recent report, using a model of spontaneous breast cancer, we have shown that bone marrow (BM)-derived myeloid progenitor cells in the premetastatic lung secrete the proteoglycan versican, which induces MET of metastatic tumor cells and accelerates metastases. This review summarizes recent progress in MET research and outlines a unique paracrine cross talk between the microenvironment and the cancer cells that promotes tumor outgrowth in the metastatic organ and discusses opportunities for novel antimetastatic approaches for cancer therapy.
doi:10.1158/0008-5472.CAN-12-1223
PMCID: PMC3649848  PMID: 23002209

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