Metastasis models: the green fluorescent revolution?
Sébastien Paris1,3 and
Richard Sesboüé2
1 Laboratory of Biochemistry and Cellular Biology, University of Namur, 61 Rue de Bruxelles, 5000 Namur, Belgium and 2 INSERM U-614, Faculté de Médecine-Pharmacie, Rouen, France
3 To whom correspondence should be addressed Email: sebastien.paris{at}fundp.ac.be
 |
Abstract
|
---|
Metastases are the leading cause of treatment failure and death of patients affected by malignant tumors, which makes them a major therapeutic target. During the last decade, efforts made to understand the mechanisms governing the passage of a localized tumor cell to a metastatic one has led to significant advances in this field. In vivo models using nude mice largely contributed to the understanding of this multi-step phenomenon, thus allowing the discovery of new targets and the development of therapeutic agents. These models were however hampered by the difficulties to detect micrometastases. The recent introduction of the green fluorescent protein (GFP) as a marker for tumor cells has radically changed the use of these models, in particular by allowing detection of single cell metastases in vivo. In this review, we discuss the major advantages of models using GFP-labeled cells and their limits.
Abbreviations: GFP, green fluorescent protein; ITI, inter-alpha trypsin inhibitor; IVM, intra-vital microscopy; IVVM, intra-vital video microscopy; o.g., orthotopic graft; RFP, red fluorescent protein; s.c., subcutaneous; TIMP, tissue inhibitor of metalloproteinase
 |
Introduction
|
---|
The metastatic process is a series of complex interactions between cancerous cells and host cells or tissues (1). A cell originating from a typical solid tumor must undergo several modifications to become metastatic. These include loss of adhesion with surrounding cells, migration towards vessels, destruction of the basement membrane, passage in the blood stream and escape from the immune system. The cells must then arrest and extravasate into the target tissue, and growth in this tissue where a neoangiogenesis leads to its blood supply. Each of these events requires that the cell acquire particular capacities and thus numerous molecular modifications, which must successively appear in the same clone. Such transformations are also dependent upon microenvironmental conditions. For example hypoxia leads to induction of the hypoxia inducible factor-1, which is over-expressed in numerous progressing cancers (2).
Many points of the metastatic process are still undefined and characterization of their molecular basis is crucial in the development of new cancer therapies. Accordingly, contemporary experiments are attempting to define molecular changes and then modify them. For example, several studies are directed towards the inhibition of angiogenesis by blocking the action of the vascular endothelial cell growth factor (reviewed in refs 3,4). Indeed, as soon as the center of a primary tumor reaches 1 mm3, it becomes hypoxic; in order to get nutrients and oxygen, the tumor has to develop new blood vessels. Thus, prevention of angiogenesis could concomitantly inhibit tumor growth and metastatic spread. Other approaches are directed towards the inhibition of matrix metalloproteinases (MMP) (reviewed in ref. 5). MMPs are involved in the modification of the extracellular matrix during tumor growth and dissemination; while cancerous cells are proliferating, they produce MMPs that degrade peritumoral tissues in order for the cells to migrate towards the blood stream and to metastasize. The use of specific inhibitors has promise because of this [e.g. TIMP (6)].
Whatever the pathway under investigation, it is essential to have at one's disposal an in vivo model mimicking as far as possible the cascade of biological events leading to the formation of metastases. This review will focus on the use of the green fluorescent protein (GFP) in metastasis models by highlighting their main advantages and by describing some of the most representative current studies. Then, we will discuss their limits and try to underline their weaknesses.
 |
The models of studies of the metastases
|
---|
Nude mice are widely used to study the metastatic process in vivo. These immunodeficient animals (7,8) may be xenografted with human cancer cells (9,10). Historically, Rygaard and Povlsen realized the first successful transplantation of a human tumor in these mice in 1969 (11). Whatever the method of cell grafting [intravenous (i.v.), subcutaneous (s.c.), orthotopic, etc.], a major problem is difficulty visualizing micrometastases in host tissues. Current methods of metastases detection are generally restricted to histology or immunohistochemical analysis of target tissues. Direct macroscopic observation of the metastases is even less sensitive. As they do not address to micrometastases, such observations considerably underestimate the actual number of metastases; further, the number of tissues reasonably analyzable limits them. Such investigations are therefore restricted to a qualitative rather than a quantitative analysis of the effect of a molecule or a gene on the metastatic process.
A technique devoted to the detection of micrometastatic foci, even to that of a single cancerous cell in healthy tissue, is to express in these cells an indicator gene such as the Escherichia coli lacZ gene (1221). Although this system allows for the visualization of small groups of cancerous cells (15), it shows several restrictions: it is very difficult to detect a single malignant cell, it is time consuming and requires a complex preparation of the samples, it is impossible to enumerate all the metastatic foci in a target organ, and the endogenous ß-galactosidase activity of some cells prevents a good interpretation of the results (22). Optical imaging via the luciferase reporter system is a good alternative (23,24), but it requires substrate delivery to the tissue under study and a special acquisition device; besides its low image resolution, this technique does detect single cells (25). These drawbacks have led to the use of the GFP as a marker for cancer cells. Initially isolated from the jellyfish Aequoria victoria (26), the GFP gene was cloned in 1992 by Prasher et al. (27). It is a compact, acid and globular 27-kDa protein, composed of 238 amino acids (28), with an excitation peak of 488 nm and an emission peak of 508 nm. Its fluorescent properties are acquired by an autocatalytic mechanism giving rise to the fluorophore, that does not require any biochemical transformation, contrast agent or the use of ionizing radiation in order to be visualized (29,30). Zolotukhin et al. obtained a humanized mutant, hGFP-S65T, that displayed a high expression level in mammalian cells (31): in comparison with wild GFP, it is 35-fold more fluorescent, and much more easily expressed in mammalian cell lines. The GFP has been expressed in a variety of cells and organisms: bacteria (32), yeast (33), eukaryotic cell lines (3436) and transgenic mice (37).
 |
The GFP as a cell marker to track metastases
|
---|
GFP has since become a reporter gene of choice. The fluorescence expressed by transfected cells allows one to select very high-level expression GFP transfectants in vitro (38). It is then very easy to follow the stability of the fluorescence during time, in non-selective medium. This can be accomplished either by direct observation using a fluorescence microscope or by cytofluorimetry. Further, fluorescence-activated cell sorting (FACS) allows for purification of a polyclonal population of GFP-labeled cells. In vivo, one of the main advantages of GFP lies in the ability to visualize single cancer cells. Hoffman's group first used this property to develop GFP-based cancer models. For example, Chishima et al. (39) stably transfected Chinese hamster ovary (CHO-K1) cells by a vector containing the cDNA of GFP. After surgical orthotopic implantation (SOI), they demonstrated for the first time that the expression of GFP in these cells allowed the detection in fresh tissue of single metastatic cells. Later on, they successfully used this system in several malignant cell lines: lung [ANIP 973 (40,41) NCI-H460 (42)] and prostate [PC-3 (43)], confirming the ability of GFP to mark cancer cells. Fluorescence is therefore the tool of choice for studies requiring a sensitive analysis of micrometastases. At present, a wide variety of human tumor cell types, including brain, breast, colon, lung, skin, pancreas, prostate and stomach, can be tracked using the GFP-expression system (Table I).
View this table:
[in this window]
[in a new window]
|
Table I. Summary of stable GFP-expressing cell lines and localization of metastasis foci (), according the species, the cell line origin and the inoculation type (i.p., intraperitoneal; i.c., intracardiac)
|
|
The major advantage of this system is that GFP-tagged living cells can be directly seen in healthy tissues of the host, without any preparation (38): the unfixed tissue can be cut into thin slices, placed between glass slides, and directly observed with fluorescence microscopy. In comparison with other techniques, such a simple method speeds up the analysis allowing one to multiply the number of experiments and tissues analyzed. Further, quantitative studies may be performed with respect to the size of the metastases observed (44).
The ability to non-invasively visualize cells is essential to study in vivo processes in real time. This property of GFP has been successfully used in experiments using intravital microscopy (IVM) (45,46), intravital video microscopy (IVVM) (4750) and whole-body imaging (5154). Kan and Liu (48) and Naumov et al. (49) demonstrated that IVVM allowed a real time direct observation of GFP-labeled cells in live animals down to the single cell level. Yang et al. developed models of whole-body visualization of the metastases in living animals (53): the metastatic evolution during time could be observed in the same animal, with arrest of malignant cells in capillaries, extravasation and growth of the metastases. Finally, IVM also allows one to follow each step involved in the metastatic process, as reviewed in (55).
Another promising technology is to use viral vectors to label cells in vivo: 47 days after cancer cell implantation in nude mice, GFP retro- (56) or adeno-viral (57) supernatants are administered and fluorescence is monitored by successive IVM; viral GFP transduction allows us to specifically follow the development and dissemination of growing tumor cells according to time.
 |
Studies enhanced by the GFP
|
---|
Analysis of gene involvement in the metastatic process
Experiments aimed at analyzing the effect of gene expression or inhibition on the metastatic process can take advantage of GFP tagging. Using the highly metastatic lung cancer cell line (GFP-labeled H460 M cells), we have demonstrated the involvement of chains of the inter-alpha trypsin inhibitor family (ITI) on tumor growth and metastatic spreading. Transfection of fluorescent cells with the cDNAs corresponding to the various chains of the ITI family allowed us to study the influence of their expression on the metastatic process and the tumor growth after s.c. injection and analysis of the number of fluorescent lung metastases (58). We showed that ITI-H1 and ITI-H3 chains significantly decreased the metastatic scattering. The ITI-L chain was able to decrease the tumor growth and the number of lung metastases, possibly through the protease inhibitory characteristics of its bikunin moiety. Other experiments also demonstrated the feasibility of such an approach for the study of gene expression: Zhang et al. showed that over-expression of the bone sialoprotein (BSP) (for review, see ref. 59) in the human breast cell line MDA-MB-231 (60) increased the number of fluorescent lung metastases while transfection with an antisense BSP sequence reduced the number of metastases. In an elegant study taking advantage of GFP-tagged lymphomas and whole-body imaging in mice, Schmitt et al. (61) examined the p53 tumor suppressor pathway and tested the contribution of apoptosis to tumor suppression.
Screening of molecules that might have an effect on metastasis
Besides several in vitro cytotoxic assays built up with GFP-transduced cells for high-throughput screening of novel antineoplastic agents (6264), various in vivo experiments have been designed to study the therapeutic potential of drugs on tumor growth and metastasis. Among several promising molecules, Manni et al. (65) demonstrated that after grafting breast cancer cells (GFP-tagged MDA-MB-435 cells), the administration of alpha-difluoromethylornithine (DFMO) significantly decreased the number of mice presenting lung metastases; further, DFMO administration also reduced local recurrence of primary tumor growth after its removal. These cells were also used to demonstrate the inhibitory properties of a truncated form of a mammalian lectin involved in metastasis, galectin-3, on tumorigenicity, tumor invasion and metastasis in vivo (66). Lawson et al. (44) showed that the use of a novel vitamin E analog, the RRR-alpha-tocopherol ether-linked acetic acid analog (alpha TEA) had an inhibitory effect on lung metastases and tumor growth in a syngeneic BALB/c mouse mammary tumor model. The drug was delivered via an aerosolized liposomal formulation and its effect was correlated with an increase in apoptosis of cells. Sun et al. demonstrated the efficacy of the camptothecin analog DX-8951f (Exatecan mesylate) against two human pancreatic tumor cell line models (67): this new molecule was found to be more effective than gemcitabine, a standard treatment for pancreatic cancer, on metastases of MIA-PaCa-2 and BxPC-3 GFP-labeled cells. The antimetastatic activity of a 2'-deoxycytidine analog, CS-862, could also be demonstrated in another pancreatic model using the red fluorescent protein (RFP) (68). Mori et al. have studied the effect of S-1, a novel oral derivative of 5-fluorouracil (5-FU), on the development of peritoneal metastases induced by GFP-tagged gastric cancer cells (MKN-45) (69); they demonstrated that the therapeutic effect of S-1 was significantly greater than that of 5-FU. Finally, a murine GFP-tagged lymphoma model has been used to study the antitumor activity of cyclophosphamide and found that it depends on its ability to induce apoptosis and senescence (70).
Activated cells
The ability to retrieve live cells by FACS after passage in vivo opens the way to new studies; the genome, the transcriptome or the proteome of these activated cells can be compared with that of parental in vitro cultivated cells and give molecular information on the metastatic process. Using this strategy, Dellacasagrande et al. (71) demonstrated that freshly sorted mouse plasmacytoma (MOPC315) GFP-labeled cells over-expressed the functional chemokine receptor CCR6. They suggested that chemotaxis via CCR6 might be a common mechanism by which malignant cells metastasize to liver that constitutively expresses CCL20, the natural CCR6 ligand.
Metastatic potential
The use of GFP and its by-products allows for dual-color studies to compare the metastatic potential of various cell lines. Glinskii et al. (72) have collected evidence demonstrating that there is a difference between cells activated after passage in vivo (GFP-tagged) and the parental cells cultivated in vitro (RFP-tagged). Having isolated and cultured circulating GFP-tagged cells obtained after orthotopic implantation, they co-injected an equivalent number of activated and parental cells and demonstrated that GFP-tagged cells have an increased metastatic propensity compared with the parental RFP-tagged cells. Dual-color studies were also performed to analyze the clonality of metastasis (73) and to follow RFP-tagged tumor cell dissemination in a GFP transgenic mouse host (74).
Dormancy
Although numerous cancerous cells have the capacity to migrate towards blood vessels (75) and to arrest in a target tissue, only a low percentage of them are able to form metastases. Studies recently realized by IVVM using GFP-labeled cells demonstrated that although the extravasation of cells is not limited, the metastatic cells do not all self renew as there are populations of dormant cells only with a potential for subsequent proliferation observed (76,77).
Kinetics
A key parameter in the study of the effect of a gene or a molecule on the metastatic process is the observation of development of metastases over time. Before the use of GFP, these studies could not be done. Using H460 MGFP cells (38), we have demonstrated that it is possible to quantify the metastatic foci present in lungs and thus to study their appearance with time. Fluorescent lung metastases are detected as soon as 2 weeks after s.c. injection, making it possible to study accurately the effect of genes, peptides or small molecules on the early steps of metastasis. A mouse bone marrow model was used to study the graft-versus-host-disease by IVM and follow cell homing and expansion according to time (78).
 |
Limits of the GFP models
|
---|
Biological reality
Generally speaking it is necessary to keep in mind that these in vivo models, based or not based on GFP, are far from the pathophysiological reality of carcinogenesis and only partially reflect the various mechanisms involved in the metastatic process. Indeed, models using experimental metastases obtained by i.v. injection of cancerous cells do not study the early stages of metastasis prior to passage into the blood stream, i.e. they are restricted to the study of late events, such as the evaluation of the dormancy or growth of malignant cells in target organs (79). On the other hand, even if most human cell lines may form primary tumors after s.c. injection, they are rarely able to produce metastases. In fact cell lines selected for their strong potential metastatic capacity have been found to be inefficient in an attempt to form spontaneous metastases after intramuscular injection (80). Among models using cancerous cells and nude mice, those using orthotopic grafts (o.g.) get closer to physiological conditions because cancerous cells are introduced in the tissue of origin. Nevertheless, certain o.g. turned out to be technically difficult; for example, the SOI of lung cancer cells requires a thoracotomy to transplant to the mouse lung a fragment of histologically intact tumoral tissue (8183). Furthermore, the quality of transplanted cells can be very diverse since primary tumors are prone to necrosis and the tumor fragment cannot be identical in each animal thus producing a highly heterogeneous number of implanted cells.
Problem of detection
Although these models have allowed remarkable progress in the detection of the micrometastases, their enumeration may still be difficult. The GFP-expression level in stably transfected cells must be high enough to make cells unambiguously distinguishable in host tissues. Moreover in liver, the tissue density hampers the fluorescence detection, thus a correct enumeration of the metastases; to get a correct evaluation of the fluorescence, the organ must be cut into slices with a thickness under 0.5 mm. This may distort the numbering of metastases with large metastasis being cut in two parts, and fluorescent cells spreading on non-malignant tissue. On the other hand, the autofluorescence of some tissues, such as lung, may hamper the analysis. Such difficulties are likely to be overcome by recent improvements in image acquisition and instrumentation (84,85).
Enhanced sensitivity
The cytotoxic activity of various anticancer drugs can be enhanced by reactive oxygen species (86,87) that can be generated by GFP (88). Goto et al. therefore hypothesized that GFP transfection could enhance the anticancer drug sensitivity of human neuroblastoma cell lines (CHLA-20 and CHLA-90). They demonstrated that GFP transfection results in an oxidative stress that enhanced the sensitivity of neuroblastoma cell lines to various anticancer drugs such as carboplatin, melphalan, doxorubicin and etoposide (89); indeed, these drugs turned out to be much less effective than expected in pre-clinical tests. Although this enhanced sensitivity has been only observed once, care should be taken when assaying new drugs with these models.
Cytotoxicity
Although GFP has been used in many cell lines with no evidence of cytotoxicity (90,91), and transgenic animals were obtained (37,92), the establishment of stable GFP cell lines has a low efficiency. Several studies showed a GFP-induced toxicity; for instance, Liu et al. demonstrated that GFP transfection in various cell lines (NIH/3T3, BHK-21, Huh7 and HepG2) by different vectors led to programmed cell death or apoptosis (93) by promoting the activation of caspase 3. The observed toxicity may also be related to the vector used as a study showed (94) that the peptide generated by the multiple cloning site of the pEGFP (enhanced green fluorescent protein)-C2 vector (Clontech) induced apoptosis and that partial or total removal of this multiple cloning site abrogated the toxicity.
Immune response
In studies requiring the use of immunocompetent mice, for instance in pre-clinical evaluation of gene therapy, the use of GFP-tagged cells raises a problem. The difficulty is that this protein can induce immune response, mediated by a high cytotoxic T lymphocyte response against GFP-expressing cells (95). Although this has no direct influence on the presented models, it must be kept in mind when imagining new applications. It is worth noting that this phenomenon was not observed in other studies (96,97), possibly because of the high metastatic potential of the cell models used.
 |
Conclusion and perspectives
|
---|
Thanks to the introduction of GFP as a marker for cancerous cells, the detection of the micrometastases down to the unicellular level has become possible. Numerous cell lines of human or mammalian origin have already been tested with this system successfully. From now on it is therefore possible to track micrometastases in a simple and fast way within various tissues such as lung, liver, brain, bone, etc. Besides its increased resolution with respect to pre-existent models, the GFP-based technology, thanks to its non-invasive character, allowed us to implement new research strategies on the metastatic process among which IVVM and whole-body imaging must be highlighted because they allow us to study in a kinetic way the evolution of the metastases in living animals (53). The GFP tag also allowed us to obtain metastatic cells activated after a passage in vivo in order to study various proteins and genes expressed in a differential way by comparison with the less aggressive parental cell line (71). The studies of genes and small anticancerous or antimetastatic molecules also took advantage of the GFP technology, because the study of their impact on these processes is made easy with a so far unequalled accuracy. They unfortunately suffer from some limitations such as, for example, the increased oxidative stress (89) induced by GFP. Results must be interpreted with caution and studies should come along with experiments determining the impact of GFP expression on the sensitivity of transfected cells for molecules or genes under investigation. Nevertheless, the interest raised by GFP models to track cancerous cells is clearly warranted and may undoubtedly lead to important developments in the next few years. Among future applications, there will be a greater use of these models for the in vivo screening of novel drugs and genes of interest. With the discovery of new targets and the progress in anticancer research, these models will certainly find a place of choice for testing new pre-clinical therapeutic strategies. Another possible purpose is the study of the homing of metastatic cells tracked by virtue of their fluorescence. Investigations on the modulation of the expression of genes supposedly involved in the homing of metastatic cells will allow us to know if there is actually a preferential change of target tissue for these cells. An interesting example to study would be that of the chemokine receptors CXCR4 and CCR7, recently involved in the homing of breast cancer metastasis (98). Efforts should also be made to study the influence of the GFP-expression on the sensitivity of cancerous cells for drugs under investigation in order to extend their possible use (89). It would also be interesting to study the reaction of dormant metastatic cells after excision of the primary tumor. Besides understanding the relationship between primary tumor cells and metastatic quiescent cells, such an investigation may allow us to estimate primary tumor recurrence and to test adjuvant therapies directed against these cells. Finally, different fluorescent labels may be combined to study the expression of a gene tagged by variants of the GFP (e.g. red fluorescent protein) under the control of a specific promoter in cells constitutively expressing GFP; the use of IVM or IVVM may then allow one to determine if and when the corresponding gene is activated during the metastatic process.
 |
Acknowledgments
|
---|
We apologize to those authors whose work we could not cite directly due to space limitations. The authors acknowledge the helpful contribution of an anonymous referee. We are indebted to Theodora S.Ross for critical review of the manuscript and to Gaëlle Bougeard-Denoyelle for her editing help.
 |
References
|
---|
- Hart,I.R. and Saini,A. (1992) Biology of tumour metastasis. Lancet, 339, 14531457.[CrossRef][ISI][Medline]
- Subarsky,P. and Hill,R.P. (2003) The hypoxic tumour microenvironment and metastatic progression. Clin. Exp. Metastasis, 20, 237250.[CrossRef][ISI][Medline]
- Ferrara,N., Gerber,H.P. and LeCouter,J. (2003) The biology of VEGF and its receptors. Nature Med., 9, 669676.[CrossRef][ISI][Medline]
- Shinkaruk,S., Bayle,M., Lain,G. and Deleris,G. (2003) Vascular endothelial cell growth factor (VEGF), an emerging target for cancer chemotherapy. Curr. Med. Chem. Anti-Cancer Agents, 3, 95117.
- Overall,C.M. and Lopez-Otin,C. (2002) Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nature Rev. Cancer, 2, 657672.[CrossRef][ISI][Medline]
- Bode,W. and Maskos,K. (2003) Structural basis of the matrix metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases. Biol. Chem., 384, 863872.[CrossRef][ISI][Medline]
- Flanagan,S.P. (1966) Nude, a new hairless gene with pleiotropic effects in the mouse. Genetic Res., 8, 295309.[ISI]
- Pantelouris,E.M. (1968) Absence of thymus in a mouse mutant. Nature, 217, 370371.[ISI][Medline]
- Fidler,I.J. (1986) Rationale and methods for the use of nude mice to study the biology and therapy of human cancer metastasis. Cancer Metastasis Rev., 5, 2949.[ISI][Medline]
- Sharkey,F.E. and Fogh,J. (1984) Considerations in the use of nude mice for cancer research. Cancer Metastasis Rev., 3, 341360.[CrossRef][ISI][Medline]
- Rygaard,J. and Povlsen,C.O. (1969) Heterotransplantation of a human malignant tumour to Nude mice. Acta Pathol. Microbiol. Scand., 77, 758760.[Medline]
- Lin,W.C., Pretlow,T.P., Pretlow,T.G.,2nd and Culp,L.A. (1990) Bacterial lacZ gene as a highly sensitive marker to detect micrometastasis formation during tumor progression. Cancer Res., 50, 28082817.[Abstract]
- Lin,W.C., Pretlow,T.P., Pretlow,T.G.,3rd and Culp,L.A. (1990) Development of micrometastases: earliest events detected with bacterial lacZ gene-tagged tumor cells. J. Natl Cancer Inst., 82, 14971503.[Abstract]
- Culp,L.A., Lin,W., Kleinman,N.R., O'Connor,K.L. and Lechner,R. (1998) Earliest steps in primary tumor formation and micrometastasis resolved with histochemical markers of gene-tagged tumor cells. J. Histochem. Cytochem., 46, 557568.[Abstract/Free Full Text]
- Culp,L.A., Lin,W.C., Kleinman,N.R., Campero,N.M., Miller,C.J. and Holleran,J.L. (1998) Tumor progression, micrometastasis and genetic instability tracked with histochemical marker genes. Prog. Histochem. Cytochem., 33, 329348.[Medline]
- Holleran,J.L., Miller,C.J., Edgehouse,N.L., Pretlow,T.P. and Culp,L.A. (2002) Differential experimental micrometastasis to lung, liver and bone with lacZ-tagged CWR22R prostate carcinoma cells. Clin. Exp. Metastasis, 19, 1724.[CrossRef][ISI][Medline]
- Zhang,L., Kharbanda,S., McLeskey,S.W. and Kern,F.G. (1999) Overexpression of fibroblast growth factor 1 in MCF-7 breast cancer cells facilitates tumor cell dissemination but does not support the development of macrometastases in the lungs or lymph nodes. Cancer Res., 59, 50235029.[Abstract/Free Full Text]
- Kruger,A., Schirrmacher,V. and Khokha,R. (19981999) The bacterial lacZ gene: an important tool for metastasis research and evaluation of new cancer therapies. Cancer Metastasis Rev., 17, 285294.[CrossRef]
- Maurer-Gebhard,M., Schmidt,M., Azemar,M., Stocklin,E., Wels,W. and Groner,B. (1999) A novel animal model for the evaluation of the efficacy of drugs directed against the ErbB2 receptor on metastasis formation. Hybridoma, 18, 6975.[ISI][Medline]
- Kobayashi,K., Nakanishi,H., Masuda,A., Tezuka,N., Mutai,M. and Tatematsu,M. (1997) Sequential observation of micrometastasis formation by bacterial lacZ gene-tagged Lewis lung carcinoma cells. Cancer Lett., 112, 191198.[CrossRef][ISI][Medline]
- Brunner,N., Thompson,E.W., Spang-Thomsen,M., Rygaard,J., Dano,K. and Zwiebel,J.A. (1992) lacZ transduced human breast cancer xenografts as an in vivo model for the study of invasion and metastasis. Eur. J. Cancer, 28A, 19891995.[CrossRef][ISI][Medline]
- Zdenek,L. (1970) Indigogenic methods for glycosidases. I. An improved method for beta-D-galactosidase and its application to localization studies of the enzymes in the intestine and in other tissues. Histochemie, 23, 289294.[CrossRef][ISI][Medline]
- Vooijs,M., Jonkers,J., Lyons,S. and Berns,A. (2002) Noninvasive imaging of spontaneous retinoblastoma pathway-dependent tumors in mice. Cancer Res., 62, 18621867.[Abstract/Free Full Text]
- Adams,J.Y., Johnson,M., Sato,M., Berger,F., Gambhir,S.S., Carey,M., Iruela-Arispe,M.L. and Wu,L. (2002) Visualization of advanced human prostate cancer lesions in living mice by a targeted gene transfer vector and optical imaging. Nature Med., 8, 891897.[ISI][Medline]
- Hoffman,R. (2002) Green fluorescent protein imaging of tumour growth, metastasis and angiogenesis in mouse models. Lancet Oncol., 3, 546556.[CrossRef][ISI][Medline]
- Shimomura,O., Johnson,F.H. and Saiga,Y. (1962) Extraction, purification and properties of aequorin, a bioluminescent protein from the luminous hydromedusan, Aequorea. J. Cell Comp. Physiol., 59, 223239.[ISI]
- Prasher,D.C., Eckenrode,V.K., Ward,W.W., Prendergast,F.G. and Cormier,M.J. (1992) Primary structure of the Aequorea victoria green-fluorescent protein. Gene, 111, 229233.[CrossRef][ISI][Medline]
- Yang,F., Moss,L.G. and Phillips,G.N.,Jr (1996) The molecular structure of green fluorescent protein. Nat. Biotechnol., 14, 12461251.[ISI][Medline]
- Cody,C.W., Prasher,D.C., Westler,W.M., Prendergast,F.G. and Ward,W.W. (1993) Chemical structure of the hexapeptide chromophore of the Aequorea green-fluorescent protein. Biochemistry, 32, 12121218.[ISI][Medline]
- Hoffman,R.M. (2002) Green fluorescent protein imaging of tumor cells in mice. Lab. Anim. (NY), 31, 3441.
- Zolotukhin,S., Potter,M., Hauswirth,W.W., Guy,J. and Muzyczka,N. (1996) A humanized green fluorescent protein cDNA adapted for high-level expression in mammalian cells. J. Virol., 70, 46464654.[Abstract]
- Feilmeier,B.J., Iseminger,G., Schroeder,D., Webber,H. and Phillips,G.J. (2000) Green fluorescent protein functions as a reporter for protein localization in Escherichia coli. J. Bacteriol., 182, 40684076.[Abstract/Free Full Text]
- Shulga,N., Mosammaparast,N., Wozniak,R. and Goldfarb,D.S. (2000) Yeast nucleoporins involved in passive nuclear envelope permeability. J. Cell. Biol., 149, 10271038.[Abstract/Free Full Text]
- Chalfie,M., Tu,Y., Euskirchen,G., Ward,W.W. and Prasher,D.C. (1994) Green fluorescent protein as a marker for gene expression. Science, 263, 802805.[ISI][Medline]
- Cheng,L., Du,C., Murray,D., Tong,X., Zhang,Y.A., Chen,B.P. and Hawley,R.G. (1997) A GFP reporter system to assess gene transfer and expression in human hematopoietic progenitor cells. Gene Ther., 4, 10131022.[CrossRef][ISI][Medline]
- Cheng,L., Fu,J., Tsukamoto,A. and Hawley,R.G. (1996) Use of green fluorescent protein variants to monitor gene transfer and expression in mammalian cells. Nat. Biotechnol., 14, 606609.[ISI][Medline]
- Okabe,M., Ikawa,M., Kominami,K., Nakanishi,T. and Nishimune,Y. (1997) Green mice as a source of ubiquitous green cells. FEBS Lett., 407, 313319.[CrossRef][ISI][Medline]
- Paris,S., Chauzy,C., Martin-Vandelet,N., Delpech,B., Thiberville,L., Martin,J.P. and Diarra-Mehrpour,M. (1999) A model of spontaneous lung metastases visualised in fresh host issue by green fluorescent protein expression. Clin. Exp. Metastasis, 17, 817822.[CrossRef][ISI][Medline]
- Chishima,T., Miyagi,Y., Wang,X., Yamaoka,H., Shimada,H., Moossa,A.R. and Hoffman,R.M. (1997) Cancer invasion and micrometastasis visualized in live tissue by green fluorescent protein expression. Cancer Res., 57, 20422047.[Abstract]
- Chishima,T., Miyagi,Y., Wang,X., Tan,Y., Shimada,H., Moossa,A. and Hoffman,R.M. (1997) Visualization of the metastatic process by green fluorescent protein expression. Anticancer Res., 17, 23772384.[ISI][Medline]
- Chishima,T., Miyagi,Y., Wang,X., Baranov,E., Tan,Y., Shimada,H., Moossa,A.R. and Hoffman,R.M. (1997) Metastatic patterns of lung cancer visualized live and in process by green fluorescence protein expression. Clin. Exp. Metastasis, 15, 547552.[CrossRef][ISI][Medline]
- Yang,M., Hasegawa,S., Jiang,P., Wang,X., Tan,Y., Chishima,T., Shimada,H., Moossa,A.R. and Hoffman,R.M. (1998) Widespread skeletal metastatic potential of human lung cancer revealed by green fluorescent protein expression. Cancer Res., 58, 42174221.[Abstract]
- Yang,M., Jiang,P., Sun,F.X., Hasegawa,S., Baranov,E., Chishima,T., Shimada,H., Moossa,A.R. and Hoffman,R.M. (1999) A fluorescent orthotopic bone metastasis model of human prostate cancer. Cancer Res., 59, 781786.[Abstract/Free Full Text]
- Lawson,K.A., Anderson,K., Menchaca,M., Atkinson,J., Sun,L., Knight,V., Gilbert,B.E., Conti,C., Sanders,B.G. and Kline,K. (2003) Novel vitamin E analogue decreases syngeneic mouse mammary tumor burden and reduces lung metastasis. Mol. Cancer Ther., 2, 437444.[Abstract/Free Full Text]
- Sturm,J.W., Keese,M.A., Petruch,B., Bonninghoff,R.G., Zhang,H., Gretz,N., Hafner,M., Post,S. and McCuskey,R.S. (2003) Enhanced green fluorescent protein-transfection of murine colon carcinoma cells: key for early tumor detection and quantification. Clin. Exp. Metastasis, 20, 395405.[CrossRef][ISI][Medline]
- Kikkawa,H., Kaihou,M., Horaguchi,N. et al. (2002) Role of integrin alpha (v)beta3 in the early phase of liver metastasis: PET IVM analyses. Clin. Exp. Metastasis, 19, 717725.[CrossRef][ISI][Medline]
- Mook,O.R., Van Marle,J., Vreeling-Sindelarova,H., Jonges,R., Frederiks,W.M. and Van Noorden,C.J. (2003) Visualization of early events in tumor formation of eGFP-transfected rat colon cancer cells in liver. Hepatology, 38, 295304.[ISI][Medline]
- Kan,Z. and Liu,T.J. (1999) Video microscopy of tumor metastasis: using the green fluorescent protein (GFP) gene as a cancer-cell-labeling system. Clin. Exp. Metastasis, 17, 4955.[ISI][Medline]
- Naumov,G.N., Wilson,S.M., MacDonald,I.C., Schmidt,E.E., Morris,V.L., Groom,A.C., Hoffman,R.M. and Chambers,A.F. (1999) Cellular expression of green fluorescent protein, coupled with high-resolution in vivo videomicroscopy, to monitor steps in tumor metastasis. Cell Sci., 112 (Pt 12), 18351842.[Abstract/Free Full Text]
- Ito,S., Nakanishi,H., Ikehara,Y., Kato,T., Kasai,Y., Ito,K., Akiyama,S., Nakao,A. and Tatematsu,M. (2001) Real-time observation of micrometastasis formation in the living mouse liver using a green fluorescent protein gene-tagged rat tongue carcinoma cell line. Int. J. Cancer, 93, 212217.[CrossRef][ISI][Medline]
- Yamamoto,N., Yang,M., Jiang,P., Tsuchiya,H., Tomita,K., Moossa,A.R. and Hoffman,R.M. (2003) Real-time GFP imaging of spontaneous HT-1080 fibrosarcoma lung metastases. Clin. Exp. Metastasis, 20, 181185.[CrossRef][ISI][Medline]
- Wang,J.W., Yang,M., Wang,X., Sun,F.X., Li,X.M., Yagi,S. and Hoffman,R.M. (2003) Antimetastatic efficacy of oral 5-FU imaged by green fluorescent protein in real time. Anticancer Res., 23, 16.[ISI][Medline]
- Yang,M., Baranov,E., Jiang,P. et al. (2000) Whole-body optical imaging of green fluorescent protein-expressing tumors and metastases. Proc. Natl Acad. Sci. USA, 97, 12061211.[Abstract/Free Full Text]
- Bouvet,M., Wang,J., Nardin,S.R., Nassirpour,R., Yang,M., Baranov,E., Jiang,P., Moossa,A.R. and Hoffman,R.M. (2002) Real-time optical imaging of primary tumor growth and multiple metastatic events in a pancreatic cancer orthotopic model. Cancer Res., 62, 15341540.[Abstract/Free Full Text]
- Condeelis,J. and Segall,J.E. (2003) Intravital imaging of cell movement in tumours. Nature Rev. Cancer, 3, 921930.[CrossRef][ISI][Medline]
- Hasegawa,S., Yang,M., Chishima,T., Miyagi,Y., Shimada,H., Moossa,A.R. and Hoffman,R.M. (2000) In vivo tumor delivery of the green fluorescent protein gene to report future occurrence of metastasis. Cancer Gene Ther., 7, 13361340.[CrossRef][ISI][Medline]
- Chaudhuri,T.R., Cao,Z., Krasnykh,V.N., Stargel,A.V., Belousova,N., Partridge,E.E. and Zinn,K.R. (2003) Blood-based screening and light based imaging for the early detection and monitoring of ovarian cancer xenografts. Technol. Cancer Res. Treat., 2, 171180.[ISI][Medline]
- Paris,S., Sesboue,R., Delpech,B., Chauzy,C., Thiberville,L., Martin,J.P., Frebourg,T. and Diarra-Mehrpour,M. (2002) Inhibition of tumor growth and metastatic spreading by overexpression of inter-alpha-trypsin inhibitor family chains. Int. J. Cancer, 97, 615620.[CrossRef][ISI][Medline]
- Ganss,B., Kim,R.H. and Sodek,J. (1999) Bone sialoprotein. Crit. Rev. Oral Biol. Med., 10, 7998.[Abstract]
- Zhang,J.H., Tang,J., Wang,J., Ma,W., Zheng,W., Yoneda,T. and Chen,J. (2003) Over-expression of bone sialoprotein enhances bone metastasis of human breast cancer cells in a mouse model. Int. J. Oncol., 23, 10431048.[ISI][Medline]
- Schmitt,C.A., Fridman,J.S., Yang,M., Baranov,E., Hoffman,R.M. and Lowe,S.W. (2002) Dissecting p53 tumor suppressor functions in vivo. Cancer Cell, 1, 289298.[CrossRef][ISI][Medline]
- Torrance,C.J., Agrawal,V., Vogelstein,B. and Kinzler,K.W. (2001) Use of isogenic human cancer cells for high-throughput screening and drug discovery. Nat. Biotechnol., 19, 940945.[CrossRef][ISI][Medline]
- Izycki,D., Gryska,K., Grabarczyk,P., Wysocki,P.J., Jarosinska,A., Nawrocki,S., Kowalczyk,D.W. and Mackiewicz,A. (2001) Flow cytometric cytotoxicity assay with GFP gene modified target cells. Adv. Exp. Med. Biol., 495, 429434.[ISI][Medline]
- Steff,A.M., Fortin,M., Arguin,C. and Hugo,P. (2001) Detection of a decrease in green fluorescent protein fluorescence for the monitoring of cell death: an assay amenable to high-throughput screening technologies. Cytometry, 45, 237243.[CrossRef][ISI][Medline]
- Manni,A., Washington,S., Craig,L. et al. (2003) Effects of alpha-difluoromethylornithine on local recurrence and pulmonary metastasis from MDA-MB-435 breast cancer xenografts in nude mice. Clin. Exp. Metastasis, 20, 321325.[CrossRef][ISI][Medline]
- John,C.M., Leffler,H., Kahl-Knutsson,B., Svensson,I. and Jarvis,G.A. (2003) Truncated galectin-3 inhibits tumor growth and metastasis in orthotopic nude mouse model of human breast cancer. Clin. Cancer Res., 9, 23742383.[Abstract/Free Full Text]
- Sun,F.X., Tohgo,A., Bouvet,M., Yagi,S., Nassirpour,R., Moossa,A.R. and Hoffman,R.M. (2003) Efficacy of camptothecin analog DX-8951f (Exatecan Mesylate) on human pancreatic cancer in an orthotopic metastatic model. Cancer Res., 63, 8085.[Abstract/Free Full Text]
- Katz,M.H., Bouvet,M., Takimoto,S., Spivack,D., Moossa,A.R. and Hoffman,R.M. (2003) Selective antimetastatic activity of cytosine analog CS-682 in a red fluorescent protein orthotopic model of pancreatic cancer. Cancer Res., 63, 55215525.[Abstract/Free Full Text]
- Mori,T., Fujiwara,Y., Yano,M., Tamura,S., Yasuda,T., Takiguchi,S. and Monden,M. (2003) Prevention of peritoneal metastasis of human gastric cancer cells in nude mice by S-1, a novel oral derivative of 5-fluorouracil. Oncology, 64, 176182.[CrossRef][ISI][Medline]
- Schmitt,C.A., Fridman,J.S., Yang,M., Lee,S., Baranov,E., Hoffman,R.M. and Lowe,S.W. (2002) A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell, 109, 335346.[ISI][Medline]
- Dellacasagrande,J., Schreurs,O.J., Hofgaard,P.O., Omholt,H., Steinsvoll,S., Schenck,K., Bogen,B. and Dembic,Z. (2003) Liver metastasis of cancer facilitated by chemokine receptor CCR6. Scand. J. Immunol., 57, 534544.[CrossRef][ISI][Medline]
- Glinskii,A.B., Smith,B.A., Jiang,P., Li,X.M., Yang,M., Hoffman,R.M. and Glinsky,G.V. (2003) Viable circulating metastatic cells produced in orthotopic but not ectopic prostate cancer models. Cancer Res., 63, 42394243.[Abstract/Free Full Text]
- Yamamoto,N., Yang,M., Jiang,P., Xu,M., Tsuchiya,H., Tomita,K., Moossa,A.R. and Hoffman,R.M. (2003) Determination of clonality of metastasis by cell-specific color-coded fluorescent-protein imaging. Cancer Res., 63, 77857790.[Abstract/Free Full Text]
- Yang,M., Li,L., Jiang,P., Moossa,A.R., Penman,S. and Hoffman,R.M. (2003) Dual-color fluorescence imaging distinguishes tumor cells from induced host angiogenic vessels and stromal cells. Proc. Natl Acad. Sci. USA, 100, 1425914262.[Abstract/Free Full Text]
- Schmidt,C.M., Settle,S.L., Keene,J.L., Westlin,W.F., Nickols,G.A. and Griggs,D.W. (1999) Characterization of spontaneous metastasis in an aggressive breast carcinoma model using flow cytometry. Clin. Exp. Metastasis, 17, 537544.[CrossRef][ISI][Medline]
- Morris,V.L., Schmidt,E.E., MacDonald,I.C., Groom,A.C. and Chambers,A.F. (1997) Sequential steps in hematogenous metastasis of cancer cells studied by in vivo videomicroscopy. Invasion Metastasis, 17, 281296.[Medline]
- Goodison,S., Kawai,K., Hihara,J., Jiang,P., Yang,M., Urquidi,V., Hoffman,R.M. and Tarin,D. (2003) Prolonged dormancy and site-specific growth potential of cancer cells spontaneously disseminated from nonmetastatic breast tumors as revealed by labeling with green fluorescent protein. Clin. Cancer Res., 9, 38083814.[Abstract/Free Full Text]
- Panoskaltsis-Mortari,A., Price,A., Hermanson,J.R., Taras,E., Lees,C., Serody,J.S. and Blazar,B.R. (2004) In vivo imaging of graft-versus-host-disease in mice. Blood, 103, 35903598.[Abstract/Free Full Text]
- Price,J.E. (1990) The biology of cancer metastasis. Prog. Clin. Biol. Res., 354A, 237255.[Medline]
- Weiss,L., Mayhew,E., Rapp,D.G. and Holmes,J.C. (1982) Metastatic inefficiency in mice bearing B16 melanomas. Br. J. Cancer, 45, 4453.[ISI][Medline]
- Wang,X., Fu,X. and Hoffman,R.M. (1992) A patient-like metastasizing model of human lung adenocarcinoma constructed via thoracotomy in nude mice. Anticancer Res., 12, 13991401.[ISI][Medline]
- Wang,X., Fu,X. and Hoffman,R.M. (1992) A new patient-like metastatic model of human lung cancer constructed orthotopically with intact tissue via thoracotomy in immunodeficient mice. Int. J. Cancer, 51, 992995.[ISI][Medline]
- Wang,X., Fu,X., Kubota,T. and Hoffman,R.M. (1992) A new patient-like metastatic model of human small-cell lung cancer constructed orthotopically with intact tissue via thoracotomy in nude mice. Anticancer Res., 12, 14031406.[ISI][Medline]
- Wack,S., Hajri,A., Heisel,F., Sowinska,M., Berger,C., Whelan,M., Marescaux,J. and Aprahamian,M. (2003) Feasibility, sensitivity and reliability of laser-induced fluorescence imaging of green fluorescent protein-expressing tumors in vivo. Mol. Ther., 7, 765773.[CrossRef][ISI][Medline]
- Troy,T., Jekic-McMullen,D. Sambucetti,L. and Rice,B. (2004) Quantitative comparison of the sensitivity of detection of fluorescent and bioluminescent reporters in animal models. Mol. Imaging, 3, 923.[CrossRef][Medline]
- Troyano,A., Fernandez,C., Sancho,P., de Blas,E. and Aller,P. (2001) Effect of glutathione depletion on antitumor drug toxicity (apoptosis and necrosis) in U-937 human promonocytic cells. The role of intracellular oxidation. J. Biol. Chem., 276, 4710747115.[Abstract/Free Full Text]
- Kovacic,P. and Osuna,J.A.,Jr (2000) Mechanisms of anti-cancer agents: emphasis on oxidative stress and electron transfer. Curr. Pharm. Des., 6, 277309.[ISI][Medline]
- Greenbaum,L., Rothmann,C., Lavie,R. and Malik,Z. (2000) Green fluorescent protein photobleaching: a model for protein damage by endogenous and exogenous singlet oxygen. Biol. Chem., 381, 12511258.[ISI][Medline]
- Goto,H., Yang,B., Petersen,D., Pepper,K.A., Alfaro,P.A., Kohn,D.B. and Reynolds,C.P. (2003) Transduction of green fluorescent protein increased oxidative stress and enhanced sensitivity to cytotoxic drugs in neuroblastoma cell lines. Mol. Cancer Ther., 2, 911917.[Abstract/Free Full Text]
- Wahlfors,J., Loimas,S., Pasanen,T. and Hakkarainen,T. (2001) Green fluorescent protein (GFP) fusion constructs in gene therapy research. Histochem. Cell Biol., 115, 5965.[ISI][Medline]
- Marshall,J., Molloy,R., Moss,G.W., Howe,J.R. and Hughes,T.E. (1995) The jellyfish green fluorescent protein: a new tool for studying ion channel expression and function. Neuron, 14, 211215.[ISI][Medline]
- Yuan,X., Chittajallu,R., Belachew,S., Anderson,S., McBain,C.J. and Gallo,V. (2002) Expression of the green fluorescent protein in the oligodendrocyte lineage: a transgenic mouse for developmental and physiological studies. J. Neurosci. Res., 70, 529545.[CrossRef][ISI][Medline]
- Liu,H.S., Jan,M.S., Chou,C.K., Chen,P.H. and Ke,N.J. (1999) Is green fluorescent protein toxic to the living cells? Biochem. Biophys. Res. Commun., 260, 712717.[CrossRef][ISI][Medline]
- Endemann,G., Schechtman,D. and Mochly-Rosen,D. (2003) Cytotoxicity of pEGFP vector is due to residues encoded by multiple cloning site. Anal. Biochem., 313, 345347.[CrossRef][ISI][Medline]
- Steinbauer,M., Guba,M., Cernaianu,G., Kohl,G., Cetto,M., Kunz-Schughart,L.A., Geissler,E.K., Falk,W. and Jauch,K.W. (2003) GFP-transfected tumor cells are useful in examining early metastasis in vivo, but immune reaction precludes long-term tumor development studies in immunocompetent mice. Clin. Exp. Metastasis, 20, 135141.[CrossRef][ISI][Medline]
- Yang,M., Jiang,P., An,Z. et al. (1999) Genetically fluorescent melanoma bone and organ metastasis models. Clin. Cancer Res., 5, 35493559.[Abstract/Free Full Text]
- Rashidi,B., Yang,M., Jiang,P., Baranov,E., An,Z., Wang,X., Moossa,A.R. and Hoffman,R.M. (2000) A highly metastatic Lewis lung carcinoma orthotopic green fluorescent protein model. Clin. Exp. Metastasis, 18, 5760.[CrossRef][ISI][Medline]
- Muller,A., Homey,B., Soto,H. et al. (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature, 410, 5056.[CrossRef][ISI][Medline]
- MacDonald,T.J., Tabrizi,P., Shimada,H., Zlokovic,B.V. and Laug,W.E. (1998) Detection of brain tumor invasion and micrometastasis in vivo by expression of enhanced green fluorescent protein. Neurosurgery, 43, 14331437.
- Peyruchaud,O., Winding,B., Pecheur,I., Serre,C.M., Delmas,P. and Clezardin,P. (2001) Early detection of bone metastases in a murine model using fluorescent human breast cancer cells: application to the use of the bisphosphonate zoledronic acid in the treatment of osteolytic lesions. J. Bone Miner. Res., 16, 20272034.[ISI][Medline]
- Kim,M., Carman,C.V. and Springer,T.A. (2003) Bidirectional transmembrane signaling by cytoplasmic domain separation in integrins. Science, 301, 17201725.[Abstract/Free Full Text]
- Harms,J.E. and Welch,D.R. (2003) MDA-MB-435 human breast carcinoma metastasis to bone. Clin. Exp. Metastasis, 20, 327334.[CrossRef][ISI][Medline]
- Li,X., Wang,J., An,Z., Yang,M., Baranov,E., Jiang,P., Sun,F., Moossa,A.R. and Hoffman,R.M. (2002) Optically imageable metastatic model of human breast cancer. Clin. Exp. Metastasis, 19, 347350.[CrossRef][ISI][Medline]
- Shintani,S., Mihara,M., Nakahara,Y., Aida,T., Tachikawa,T. and Hamakawa,H. (2002) Lymph node metastasis of oral cancer visualized in live tissue by green fluorescent protein expression. Oral Oncol., 38, 664669.[CrossRef][ISI][Medline]
- Shinji,S., Ishiwata,T., Tajiri,T., Tanaka,N., Seya,T., Kawahara,K., Yokoyama,M. and Naito,Z. (2003) External whole-body image of EGFP gene expression. J. Nippon Med. Sch., 70, 462463.[CrossRef][Medline]
- Al-Mehdi,A.B., Tozawa,K., Fisher,A.B., Shientag,L., Lee,A. and Muschel,R.J. (2000) Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis. Nature Med., 6, 100102.[CrossRef][ISI][Medline]
- Hastings,R.H., Burton,D.W., Summers-Torres,D., Quintana,R., Biederman,E. and Deftos,L.J. (2000) Splenic, thymic, bony and lymph node metastases from orthotopic human lung carcinomas in immunocompromised mice. Anticancer Res., 20, 36253629.[ISI][Medline]
- Chishima,T., Yang,M., Miyagi,Y., Li,L., Tan,Y., Baranov,E., Shimada,H., Moossa,A.R., Penman,S. and Hoffman,R.M. (1997) Governing step of metastasis visualized in vitro. Proc. Natl Acad. Sci. USA, 94, 1157311576.[Abstract/Free Full Text]
- Goldberg,S.F., Harms,J.F., Quon,K. and Welch,D.R. (1999) Metastasis-suppressed C8161 melanoma cells arrest in lung but fail to proliferate. Clin. Exp. Metastasis, 17, 601607.[CrossRef][ISI][Medline]
- Moats,R., Ma,L.Q., Wajed,R., Sugiura,Y., Lazaryev,A., Tyszka,M., Jacobs,R., Fraser,S., Nelson,M.D.,Jr and DeClerck,Y.A. (2000) Magnetic resonance imaging for the evaluation of a novel metastatic orthotopic model of human neuroblastoma in immunodeficient mice. Clin. Exp. Metastasis, 18, 455461.[CrossRef][ISI][Medline]
- Bouvet,M., Nardin,S.R., Burton,D.W. et al. (2002) Parathyroid hormone-related protein as a novel tumor marker in pancreatic adenocarcinoma. Pancreas, 24, 284290.[CrossRef][ISI][Medline]
- Lee,N.C., Bouvet,M., Nardin,S., Jiang,P., Baranov,E., Rashidi,B., Yang,M., Wang,X., Moossa,A.R. and Hoffman,R.M. (2000) Antimetastatic efficacy of adjuvant gemcitabine in a pancreatic cancer orthotopic model. Clin. Exp. Metastasis, 18, 379384.[CrossRef][ISI][Medline]
- Bouvet,M., Yang,M., Nardin,S., Wang,X., Jiang,P., Baranov,E., Moossa,A.R. and Hoffman,R.M. (2000) Chronologically-specific metastatic targeting of human pancreatic tumors in orthotopic models. Clin. Exp. Metastasis, 18, 213218.[CrossRef][ISI][Medline]
- Tso,C.L., McBride,W.H., Sun,J. et al. (2000) Androgen deprivation induces selective outgrowth of aggressive hormone-refractory prostate cancer clones expressing distinct cellular and molecular properties not present in parental androgen-dependent cancer cells. Cancer J., 6, 220233.[ISI][Medline]
- Patel,B.J., Pantuck,A.J., Zisman,A. et al. (2000) CL1-GFP: an androgen independent metastatic tumor model for prostate cancer. J. Urol., 164, 14201425.[CrossRef][ISI][Medline]
- Maeda,H., Segawa,T., Kamoto,T., Yoshida,H., Kakizuka,A., Ogawa,O. and Kakehi,Y. (2000) Rapid detection of candidate metastatic foci in the orthotopic inoculation model of androgen-sensitive prostate cancer cells introduced with green fluorescent protein. Prostate, 45, 335340.[CrossRef][ISI][Medline]
- Mochizuki,Y., Nakanishi,H., Kodera,Y., Ito,S., Yamamura,Y., Kato,T., Hibi,K., Akiyama,S., Nakao,A. and Tatematsu,M. (2004) TNF-alpha promotes progression of peritoneal metastasis as demonstrated using a green fluorescence protein (GFP)-tagged human gastric cancer cell line. Clin. Exp. Metastasis, 21, 3947.[CrossRef][ISI][Medline]
- Kaneko,K., Yano,M., Tsujinaka,T., Morita,S., Taniguchi,M., Fujiwara,Y., Doki,Y., Inoue,M., Shiozaki,H. and Monden,M. (2000) Establishment of a visible peritoneal micrometastatic model from a gastric adenocarcinoma cell line by green fluorescent protein. Int. J. Oncol., 16, 893898.[ISI][Medline]
- Yang,M., Chishima,T., Wang,X., Baranov,E., Shimada,H., Moossa,A.R. and Hoffman,R.M. (1999) Multi-organ metastatic capability of Chinese hamster ovary cells revealed by green fluorescent protein (GFP) expression. Clin. Exp. Metastasis, 17, 417422.[CrossRef][ISI][Medline]
- Guba,M., Cernaianu,G., Koehl,G., Geissler,E.K., Jauch,K.W., Anthuber,M., Falk,W. and Steinbauer,M. (2001) A primary tumor promotes dormancy of solitary tumor cells before inhibiting angiogenesis. Cancer Res., 61, 55755579.[Abstract/Free Full Text]
- Harmey,J.H., Bucana,C.D., Lu,W., Byrne,A.M., McDonnell,S., Lynch,C., Bouchier-Hayes,D. and Dong,Z. (2002) Lipopolysaccharide-induced metastatic growth is associated with increased angiogenesis, vascular permeability and tumor cell invasion. Int. J. Cancer, 101, 415422.[CrossRef][ISI][Medline]
- Wong,C.W., Song,C., Grimes,M.M., Fu,W., Dewhirst,M.W., Muschel,R.J. and Al-Mehdi,A.B. (2002) Intravascular location of breast cancer cells after spontaneous metastasis to the lung. Am. J. Pathol., 161, 749753.[Abstract/Free Full Text]
- Li,C.Y., Shan,S., Huang,Q., Braun,R.D., Lanzen,J., Hu,K., Lin,P. and Dewhirst,M.W. (2000) Initial stages of tumor cell-induced angiogenesis: evaluation via skin window chambers in rodent models. J. Natl Cancer Inst., 92, 143147.[Abstract/Free Full Text]
- Wunderbaldinger,P., Josephson,L., Bremer,C., Moore,A. and Weissleder,R. (2002) Detection of lymph node metastases by contrast-enhanced MRI in an experimental model. Magn. Reson. Med., 47, 292297.[CrossRef][ISI][Medline]
- Moore,A., Sergeyev,N., Bredow,S. and Weissleder,R. (19981999) A model system to quantitate tumor burden in locoregional lymph nodes during cancer spread. Invasion Metastasis, 18, 192197.[CrossRef]
- Wyckoff,J.B., Jones,J.G., Condeelis,J.S. and Segall,J.E. (2000) A critical step in metastasis: in vivo analysis of intravasation at the primary tumor. Cancer Res., 60, 25042511.[Abstract/Free Full Text]
- Farina,K.L., Wyckoff,J.B., Rivera,J., Lee,H., Segall,J.E., Condeelis,J.S. and Jones,J.G. (1998) Cell motility of tumor cells visualized in living intact primary tumors using green fluorescent protein. Cancer Res., 58, 25282532.[Abstract]
Received December 18, 2003;
revised May 19, 2004;
accepted June 15, 2004.