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Tumor Biology |
Departments of Medical Biophysics [M. D. C., E. E. S., K. V. N., V. L. M., A. C. G., A. F. C., I. C. M.], Microbiology and Immunology [V. L. M., A. F. C.], and Oncology [V. L. M., A. F. C.], University of Western Ontario, and London Regional Cancer Centre [N. K., A. F. C.], London, Ontario, Canada N6A 4L6
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSRegional Variation in Metastatic...DISCUSSIONREFERENCES |
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Metastatic inefficiency may also vary depending on location within an organ. In mouse liver, extravasated rhabdomyosarcoma cells have been shown to migrate to the subcapsular region before cell division begins (10 , 11) , and the majority of metastases are located at the surface rather than in the interior (9 , 12) . Moreover, when migration to the surface is inhibited, there is a corresponding decrease in number of metastatic foci (11) . In chick CAM (the respiratory organ of the embryo), most extravasated murine melanoma cells migrate preferentially to arterioles, wrap around them, and replicate there (13 , 14) .
In mouse, it has been reported that cancer cells injected into the tail vein arrive via the blood stream at random distances from the outer surface of the lung, but metastases are located primarily at the surface or near major structures in the interior, 2 weeks after injection (15, 16, 17) . It is not known, however, whether this preferential distribution is due to destruction of solitary cells at some sites before growth begins, initiation of cell division at preferred sites, or continued growth only at preferred sites. Because the lung is the first organ encountered by cells from most primary tumors after entering the bloodstream (except for those entering the splanchnic circulation), it is a particularly vulnerable site for metastasis. It is, therefore, important to determine the rate-limiting steps affecting overall cancer cell survival and growth in lung and also those locations in the lung that affect metastatic inefficiency.
The two objectives of this study were: (a) to quantify overall tumor cell survival and growth over time during metastatsis development in mouse lung; and (b) to quantify the initial distribution and survival of individual cancer cells within the lung, as well as the initiation and continuation of cancer cell growth, in relation to the lung surface and major interior structures. By identifying the locations of cells and metastases at successive times after i.v. injection, we could determine whether a selective distribution of tumors within the organ resulted from preferential (a) initial distribution of cells, (b) cell survival, (c) initial growth to form microscopic tumors, or (d) continued growth to form visible tumors at specific sites.
We determined the survival of B16F10 melanoma cells in mouse lung at
sequential time points, from initial arrest in the microcirculation up
to 14 days later. An accounting technique using reference microspheres
(8
, 9)
was used to quantify survival of solitary cells,
small metastases, and macroscopic tumors. At early times (to day 4),
the spatial distributions of cells and small metastases relative to the
lung surface or major structures in the interior (arteries, veins, and
bronchioles 
100 µm) were determined by computer analysis of
digitized images of thick sections, whereas immunohistochemistry of
thin sections was used to assess apoptosis (TUNEL) and proliferation
(Ki-67) in solitary cells and metastases. For later times, the
proportion of tumor tissue adjacent to specific lung structures was
assessed. Our results showed that throughout the metastatic process
survival of injected cells in the lung is much greater than previously
thought. Furthermore, the initial distribution of injected cells is
uniform cells throughout the lung, and their survival and initial
growth are independent of location, whereas continued growth of early
metastases occurs at selective sites.
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MATERIALS AND METHODS |
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-MEM with added
ribonucleosides (-plus MEM; Life Technologies, Inc., Burlington,
Ontario, Canada) plus 10% FCS (Hyclone Laboratories, Logan,
UT). Subconfluent monolayers (70–80% confluency) were subcultured
every 3 days and were not maintained in culture beyond four passages.
To positively identify cells within the lung tissue, they were labeled
before injection with fluorescent nanospheres (Fluoresbrite 48-nm
diameter; Polysciences, Warrington, PA), as described
(10)
. The nanospheres remain brightly visible within
intact cells and dim only as diluted by cell division. Plating
efficiency and growth curve experiments verified that labeled cells
remained viable with unimpaired growth in vitro. For
injection, cells were trypsinized and resuspended in -plus MEM/10%
FCS; more than 95% of the cells excluded ethidium bromide, indicating
that membrane integrity was maintained (18
, 19)
. Finally,
9-µm diameter fluorescent microspheres (Bangs Laboratories Inc.,
Fishers, IN) were added to the cell suspension (cells:microspheres
5:1) for monitoring of cell survival using the cell accounting
procedure given below.
Animal Preparation
Female C57Bl/6 mice (Harlan Sprague Dawley, Indianapolis, IN),
6–8 weeks of age, were cared for in accordance with standards of the
Canadian Council on Animal Care, under an approved protocol of the
University of Western Ontario Council on Animal Care. Mice were
anesthetized using a ketamine/xylazine mixture (1.6 mg of ketamine and
0.08 mg of xylazine per 15 g of body mass) administered by i.p.
injection. A small incision was made in the abdominal midline to expose
the inferior vena cava, for injection to target the lungs. (This
procedure was used to allow direct comparison with our liver studies,
which require mesenteric vein injection, and to allow for
videomicroscopic observation in the same studies.) A suspension of
2.5 x 105 fluorescently labeled
B16F10 cells and 5 x 104
microspheres in 0.05 ml of cell culture medium was injected per mouse.
Buprenorphrine analgesic (0.03 mg/kg) was given s.c. as mice awoke and
also 18 h after surgery. Mice were killed at 1 h and at
various times up to 14 days after injection; lungs were fixed in 10%
neutral buffered formalin (pH 7.6). The surfaces of intact lung were
examined by episcopic fluorescence microscopy to determine numbers of
reference microspheres, solitary cells (which retain fluorescent
nanospheres in the absence of cell division), and metastases, for
assessment of cell survival and tumor progression (see below). Thick
sections (100–150 µm) were used for analysis of overall survival and
the spatial distribution of solitary cells and metastases at early time
points. Thin sections (4 µm) were processed for tissue staining and
quantitative stereology.
Quantification of the Time Course of Cell Survival and Metastatic
Growth
To assess survival of cancer cells at any time following
injection, it is necessary to compare the number of cells remaining in
the tissue at any location with the number of cells originally arriving
at the time of injection. This was done using our cell accounting
technique (8
, 9
, 20)
. Briefly, 9-µm microspheres were
mixed with the cell suspension to produce a cell:microsphere ratio of
5:1 (the precise ratio determined by placing a drop of suspension on
a coverslip and counting the numbers of cells and microspheres). On
injection, the cells and microspheres entered the perfused regions of
the lung in that proportion and were arrested in the microcirculation.
Because the microspheres are nondeformable and larger than the
capillary diameter, they became trapped by size restriction and
remained as permanent markers in the lung. This has been shown to be
true for liver (9)
and was confirmed in this study by
using the number of microspheres seen in thick (100–150 µm) sections
to estimate the numbers in the whole lungs at times up to 10 days after
injection, and comparing these values with the numbers originally
injected (data not shown). Thus, even at later times, each microsphere
observed at any location in the lung represented a known number of
cells originally arriving in that region.
The ratio of cells:microspheres in the injectate was compared with the ratio found later in lung tissue, based on counts of microspheres, metastases, and the fluorescent solitary cells. Solitary cells retaining strong nanosphere fluorescence at later times represent originally injected cells, which had not divided but remained dormant. Because small metastases originate primarily from single cells (21, 22, 23) , we could quantify their numbers as well, in relation to the numbers of cells originally injected. Each small metastasis was counted as representing the survival of a single injected cell. The percentage survival of injected cells was calculated as (cell:microsphere ratio in lung after injection)/(cell:microsphere ratio in syringe before injection) x 100%. The survival of cancer cells, thus, could be determined at any location within the lung, on initial arrest or at any subsequent time.
Proliferation and Apoptosis in Solitary Cells and Metastases
To determine whether solitary tumor cells or cells within
metastases were undergoing proliferation, apoptosis, or remaining
dormant, we used immunohistochemical staining of serial sections (4
µm) from paraffin-embedded lungs. S100 (Dako Z311) was used to
identify melanoma cells, Ki-67 (Novocastra NCL-Ki67-MM1) was used to
assess proliferation, and the TUNEL assay was used to assess apoptosis,
as described (9)
, with modifications: for S100, no antigen
retrieval was required; primary antibody was applied overnight
at room temperature (1:400 dilution); instead of using the Envision
kit, a biotinylated secondary antibody (Dako E0432) was applied,
followed by strepavidin-biotin peroxidase complex (Dako K0377). For
Ki-67, universal blocking solution (Dako CD310081) replaced normal goat
serum. Verhoeff’s iron hematoxylin elastin stain (24)
,
which stains elastic fibers and nuclei black, collagen red, muscle and
RBCs yellow, and cytoplasm gray, was used to identify vascular channels
and other anatomical structures within lung sections.
At selected time points, we examined serial sections from the lungs of at least two mice. Melanoma cells were first identified in the section stained with S100. These same cells were then assessed in adjacent serial sections for markers of proliferation and apoptosis. Percentages of melanoma cells staining for Ki-67 or TUNEL were determined for: (a) solitary cells within the tissue; and (b) cells within metastases of three size ranges: <80, 80–300, and >300 µm in diameter.
Distribution of Cell Survival and Tumor Growth Relative to Lung
Structures
Quantification of the distribution of tumor cells, small
metastases, and macroscopic tumors in relation to the lung surface and
major structures (arteries, veins, and bronchioles) in the interior was
carried out using two approaches. The first, using thick tissue
sections (100–150 µm), assessed the earlier stages of metastatic
progression, while the location of cells and small tumors could still
be represented as points. The second, using thin (4 µm)
paraffin-embedded sections, was appropriate for later stages when
tumors had grown irregularly through the tissue (days 10–14) and could
no longer be treated as points for assessing their proximity to lung
structures.
Early Stages of Tumor Progression.
The aim of this approach was to determine the location of accounting
microspheres, individual tumor cells, and developing tumors, with
respect to the lung surface and major interior structures (arteries,
veins, and bronchioles of diameter 100 µm) at successive times
after cell injection. The distances of the
microspheres/cells/metastases from the borders of the lung structures
were computed from digitized images of entire lung sections.
After fixation, the upper lobe from the right lung of each animal was
cut in half longitudinally and the lateral portion was mounted on the
cut-face for preparation of 100–150-µm thick sections (Vibratome
Series 1000; Technical Products International, St. Louis, MO). Sections
taken from at least 1-mm deep within the lung were viewed immersed in
saline using an inverted microscope. Epifluorescent illumination
allowed visualization of fluorescent cells and microspheres throughout
the entire thickness of the section, whereas oblique transillumination
provided identification of internal structures. Each field of view was
digitally captured, and overlapping fields covering the entire lung
section were combined using Adobe Photoshop 5.0 (Adobe Systems Inc.,
San Jose, CA). In this way, when using the x10 objective, a complete
image of each section could be produced based on 100 fields, at a
scale of 1 pixel/µm.
Superimposed on these images, the central positions of all microspheres, cancer cells, and metastases were marked, based on direct visual confirmation through the microscope, and treated as points. In addition, perimeters of arteries, veins, bronchioles, and the lung surface were marked on the image. The image coordinates of the points and outlines of the lung features were used to compute the distribution of distances of microspheres, cells, and metastases from the lung surface and the surface of each interior structure. Points (microspheres, cells, or small tumors) that were within 100 µm of a lung structure were considered to be "near" it. Points that fell within 100 µm of more than one lung structure were considered "near" the closest. For comparison, the analysis was also performed on a computer-generated uniform array of points superimposed on the image of each lung section to determine the proportion of points that would be expected near any particular lung structure based on a nonpreferential distribution. In this way, all points were classified as being within one of five regions: near the lung surface, arteries, veins, or bronchioles, or within the remaining tissue.
To test for nonrandom regional distribution of blood flow at the time of injection and, therefore, preferential delivery of the cancer cells within the lung, the proportion of microspheres near each of the lung structures was compared with the proportion of uniformly spaced computer-generated points in the same region. Similarly, the survival of individual cells within each region and the formation of multicellular foci were assessed.
Later Stages of Tumor Progression.
At early time points, the locations of cells, microspheres, and
multicellular foci are best treated as points for analytical purposes,
but once the tumors become large, proximity to anatomical structures
cannot be analyzed in the same way. For example, as a tumor grows at
the lung surface, its center becomes more distant from that surface.
For this reason, the degree of confluence between tumor tissue and
specific lung structures, as measured from thin sections, was used to
quantify preferential growth, as described below.
The proportion of lung volume occupied by tumor tissue (tumor burden)
immediately adjacent to the lung surface and major internal structures
was compared with the overall tumor burden for the whole lung.
Verhoeff’s stained thin sections of lung were used to identify
arteries, veins, bronchioles, and tumor tissue. Digitized composite
images based on 100 fields of view at x10 were obtained for
sections of entire lobes. The lung surface, internal structures, and
regions of tumor tissue were identified and outlined on the computer
images. From these images, the proportion of lung volume occupied by
tumor tissue was calculated by stereological analysis. [Stereology is
a well established technique commonly used in quantitative
morphological studies for obtaining 3-D information from 2-D sections
(25)
. A good explanation of the principles underlying
stereological analysis is given in Howard and Reed’s (26)
short text, recently published in association with the Royal
Microscopical Society.] Briefly, tumor burden was estimated using the
Delesse principle (25
, 26)
, which states that, on average,
the volume ratio (VV) of any component within a
reference volume (e.g., tumor within lung tissue) is equal
to the area ratio (AA) of that component exposed
in random sections (e.g., the total area of tumor profiles
relative to the overall area of the lung section). For example, if the
total section area was 50 mm2 and tumors covered
10 mm2, then 20% of the lung volume would be
occupied by tumor.
Tumor burden can also be calculated from LL, the proportion of the total length of randomly placed test lines, superimposed on the lung section, that falls on tumor tissue (25 , 26) . In this study, to test for preferential tumor growth at the lung surface, arteries, veins, or bronchioles, the outlines of these structures as seen in the sections were used as test lines to calculate tumor burden at those locations. For each of these structures the proportion of the overall outline length in contact with tumor tissue was then used to calculate LL, representing the tumor burden adjacent to that structure. For example, if 50% of the outline of arteries were in contact with tumor tissue, then 50% of the volume of the tissue immediately adjacent to arteries would be tumor. For random tumor growth, VV in the region bordering structures would be the same as VV for the whole lung. Thus, comparison of tumor burden adjacent to the surfaces of each of the structures (LL) with that for the whole lung (AA) provided an index of preferential growth at the structure surfaces.
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RESULTS |
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shows that cells can clearly be identified as having extravasated.
Survival values for fluorescent solitary cells showed a slow initial
decline from 98% at 1 h to 74% by day 3, a rapid decline to 25%
by day 4, followed by a relatively steady decline to 3.5% by days
12–14 (Fig. 2)
. In addition, counts of multicellular foci [which develop from a
subset of individual injected cells (21, 22, 23)
] contributed
an additional 8% to the overall calculation of survival at day 4 and
14% by days 6–8 and thereafter.
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. The small category included the majority of metastases found at days
4–8, but only a small proportion of those present by days 12–14.
Concurrently, medium and large categories included an increasing
proportion of metastases with time, accounting for the majority of
those lost from the small category. Thus, once micrometastases had
formed, their efficiency of progression to larger tumors was high.
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3% of solitary cells
were proliferating (Ki-67 positive) and none stained for apoptosis,
indicating that most solitary cells were dormant. Most small and all
medium and large metastases showed staining for proliferation;
regardless of size, 40% of cells within each metastasis stained
positively. No small metastases, but 20% and 80% of medium and large
metastases, respectively, showed some staining for apoptosis; for all
sizes, this involved only 1–10 cells per metastasis. Whereas this
would represent an estimated rate of apoptosis of about 1% of the
cells in the larger tumors at later times, at day 4 apoptosis was not
detected. |
Regional Variation in Metastatic Progression |
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Initial Distribution of Cells.
We first determined whether injected cells were preferentially
distributed in relation to structures within the lung. This
distribution was quantified by recording the positions of the
microspheres, which were injected along with the cells in a known ratio
and became trapped indefinitely in the pulmonary microvasculature.
Because microspheres and cells are both distributed by the blood flow
to various regions of a lung in similar proportions, the distribution
of microspheres at any time represents the initial distribution of
cells. Although the greatest number of microspheres was arrested in the
vicinity of arteries, this region comprised the greatest proportion of
the lung volume, and blood flow per unit volume of tissue did not
differ among regions. The results indicate that the delivery of cancer
cells by the blood flow to different regions of the lung was in
proportion to the volumes occupied by those regions (Fig. 4
, 
and 
).
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indicate that within each
region distributions of solitary cells and micrometastases were almost
identical to the initial cell distribution. In turn, initial cell
distribution did not differ significantly from the distribution of
available lung volume. This result indicates that survival and growth
of injected cells at day 4 were not affected by location within the
lung.
Growth of Tumor Tissue Relative to Lung Structures.
We then asked whether continued tumor growth occurred preferentially at
the lung surface and/or adjacent to specific structures within the
lung. This possibility was tested by calculating the tumor burden
adjacent to those structures, relative to the tumor burden found for
the whole lung. At day 10, when the overall tumor burden was <40%,
there had been preferential growth at the lung surface where there was
over 80% coverage. At day 14, the difference was less pronounced
(55% versus 95%), simply because there was little
room left at the surface for tumor expansion. For each of the lung
structures examined, Fig. 5
shows the tumor burden relative to that for whole lung. At day 10,
relative tumor burden was greater for arteries, veins, and lung surface
than for the whole organ (indicated by unity). However, by day 14,
relative burdens for some structures tended to decrease because the
tumor burden adjacent to them was already approaching 100%, whereas
that for the whole lung continued to increase. (Regions such as
alveoli, which are largely removed from these structures necessarily,
carried a lower burden than that averaged over the entire organ.) At
both times, tumor burden at the surface of the bronchioles was similar
to that found throughout the lung, indicating that these structures
were not supportive of preferential growth.
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DISCUSSION |
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A location dependence of metastatic progression in lung has been identified previously for murine fibrosarcoma (15) and B16F10 melanoma (16 , 17) cells. Thus, end point analysis has shown preferential development of metastases at the organ surface, although the initial distribution of arrested cells throughout the organ appeared to be uniform. Our goal was to quantify the time course and location dependence of growth of arrested cells, to determine at which stage in metastasis the preferential distribution of metastases became apparent. We found that the initial distribution of cells, with respect to the surface and internal structures, was random. The agreement between microsphere distribution and available lung volume for each separate structure demonstrated the uniformity of blood flow and, thus, uniformity of cancer cell delivery throughout the lung. At day 4, when extravasation was complete and small multicellular foci were first observed, both surviving solitary cells and metastases were distributed in the region of each lung structure in accordance with the associated volumes of tissue available. We, therefore, conclude that cancer cell deposition within the lung, survival of solitary cells after extravasation, and the initiation of cell division and formation of small multicellular foci are all location-independent processes.
Once metastases start to grow, however, proximity to the surface of major structures in the lung does have an influence on metastatic development. Continued random growth of randomly distributed micrometastases would form areas of contact with these major structures in proportion to their total surface areas and to the overall tumor growth in the organ. On the other hand, if growth were promoted at the surface of a particular structure, the proportion of that surface contacted by the tumor tissue would exceed the overall proportion of the lung volume occupied by tumors (25) . By determining the tumor burden at specific surfaces relative to the overall tumor burden of the lung, we have documented preferential tumor growth in the tissue immediately adjacent to arterial and venous vessels and, dramatically, next to the pleural surface. With continued development and growth of tumors, however, there tended to be less relative tumor burden adjacent to veins and the lung surface, as the available space at these locations became filled.
Our previous studies in other organs have indicated that cancer cells can be relatively efficient at early steps in hematogenous metastasis. Cells are carried to secondary sites, based on patterns of blood flow, where cells arrest by size restriction, based on the relative sizes of the cells and the microvasculature in that organ. Once cells have arrested, extravasation from the circulation into the tissue seems not to be rate limiting. Cells of high and low metastatic ability, and even nonmalignant cells, may extravasate equally well and with similar kinetics (8 , 10 , 11 , 14 , 27 , 29) . Quantitative assessment of cell loss suggests that the metastatic process to this point is quite efficient (8 , 9) . These conclusions were based on experiments with a variety of cell types (melanoma, mammary carcinoma, fibroblast, and rhabdomyosarcoma) in either chick embryo CAM or mouse liver. A key aspect of the present study is its demonstration that the above conclusions apply also in the lung, thus supporting the possibility that they may be of general validity throughout the body. Indeed, we showed earlier (19) that initial cell arrest and survival in the microcirculation of skeletal muscle corresponds closely to that seen in liver.
Our measurements of percentage survival of cancer cells during metastatic progression in liver and lung, from immediately after injection until 2 weeks later, show that growth of extravasated cells in target organs is considerably less efficient, and more variable, than earlier steps in the process (i.e., survival in the circulation, arrest, and extravasation). This study and our previous analysis of metastatic inefficiency in liver (9) have identified two important variables that can contribute to metastatic outcome: the proportions of cells that (a) initiate growth after extravasation, and (b) persist in growth to form metastases. However, we have found that these proportions differ markedly between B16F10 cells in lung and B16F1 cells in liver, resulting in dramatic differences in metastatic efficiency (>0.1 versus 0.0002). Understanding how the temporal and spatial interplay between cellular ("seed") and environmental ("soil") factors affect metastatic development will be important for understanding metastatic inefficiency and for development of therapies to combat metastasis (30 , 31) . Regulation of growth of cancer cells after they have extravasated offers an attractive and broad therapeutic target, and growth inhibition may be achievable by many strategies, including direct inhibition of cancer cell growth as well as control of tumor angiogenesis.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by National Cancer Institute of Canada
Grant 8133. 
3 To whom requests for reprints should be
addressed, at London Regional Cancer Centre, 790 Commissioners Road
East, London, Ontario, Canada N6A 4L6. Phone: (519) 685-8652; Fax:
(519) 685-8646; E-mail: ann.chambers{at}lrcc.on.ca
4 The abbreviations used are: CAM, chorioallantoic
membrane; TUNEL, terminal deoxynucleotidyl transferase-mediated nick
end labeling.
Received 10/25/99. Accepted 3/ 3/00.
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 B. Gu, L. Espana, O. Mendez, A. Torregrosa, and A. Sierra Organ-selective chemoresistance in metastasis from human breast cancer cells: inhibition of apoptosis, genetic variability and microenvironment at the metastatic focus Carcinogenesis, December 1, 2004; 25(12): 2293 - 2301. [Abstract] [Full Text] [PDF]
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 T.-H. Chun, F. Sabeh, I. Ota, H. Murphy, K. T. McDonagh, K. Holmbeck, H. Birkedal-Hansen, E. D. Allen, and S. J. Weiss MT1-MMP-dependent neovessel formation within the confines of the three-dimensional extracellular matrix J. Cell Biol., November 22, 2004; 167(4): 757 - 767. [Abstract] [Full Text] [PDF]
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H.-K. Yu, J.-S. Kim, H.-J. Lee, J.-H. Ahn, S.-K. Lee, S.-W. Hong, and Y. Yoon Suppression of Colorectal Cancer Liver Metastasis and Extension of Survival by Expression of Apolipoprotein(a) Kringles Cancer Res., October 1, 2004; 64(19): 7092 - 7098. [Abstract] [Full Text] [PDF]
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R. J. Ludwig, B. Boehme, M. Podda, R. Henschler, E. Jager, C. Tandi, W.-H. Boehncke, T. M. Zollner, R. Kaufmann, and J. Gille Endothelial P-Selectin as a Target of Heparin Action in Experimental Melanoma Lung Metastasis Cancer Res., April 15, 2004; 64(8): 2743 - 2750. [Abstract] [Full Text] [PDF]
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S. A. Vantyghem, C. O. Postenka, and A. F. Chambers Estrous Cycle Influences Organ-specific Metastasis of B16F10 Melanoma Cells Cancer Res., August 15, 2003; 63(16): 4763 - 4765. [Abstract] [Full Text] [PDF]
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 S. Kakiuchi, Y. Daigo, T. Tsunoda, S. Yano, S. Sone, and Y. Nakamura Genome-Wide Analysis of Organ-Preferential Metastasis of Human Small Cell Lung Cancer in Mice Mol. Cancer Res., May 1, 2003; 1(7): 485 - 499. [Abstract] [Full Text] [PDF]
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E. Barbera-Guillem, J. K. Nyhus, C. C. Wolford, C. R. Friece, and J. W. Sampsel Vascular Endothelial Growth Factor Secretion by Tumor-infiltrating Macrophages Essentially Supports Tumor Angiogenesis, and IgG Immune Complexes Potentiate the Process Cancer Res., December 1, 2002; 62(23): 7042 - 7049. [Abstract] [Full Text] [PDF]
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A. Zijlstra, R. Mellor, G. Panzarella, R. T. Aimes, J. D. Hooper, N. D. Marchenko, and J. P. Quigley A Quantitative Analysis of Rate-limiting Steps in the Metastatic Cascade Using Human-specific Real-Time Polymerase Chain Reaction Cancer Res., December 1, 2002; 62(23): 7083 - 7092. [Abstract] [Full Text] [PDF]
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Z. He, A. Ismail, L. Kriazhev, G. Sadvakassova, and A. Bateman Progranulin (PC-Cell-derived Growth Factor/Acrogranin) Regulates Invasion and Cell Survival Cancer Res., October 1, 2002; 62(19): 5590 - 5596. [Abstract] [Full Text] [PDF]
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 C. W. Wong, C. Song, M. M. Grimes, W. Fu, M. W. Dewhirst, R. J. Muschel, and A.-B. Al-Mehdi Intravascular Location of Breast Cancer Cells after Spontaneous Metastasis to the Lung Am. J. Pathol., September 1, 2002; 161(3): 749 - 753. [Abstract] [Full Text] [PDF]
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G. N. Naumov, I. C. MacDonald, P. M. Weinmeister, N. Kerkvliet, K. V. Nadkarni, S. M. Wilson, V. L. Morris, A. C. Groom, and A. F. Chambers Persistence of Solitary Mammary Carcinoma Cells in a Secondary Site: A Possible Contributor to Dormancy Cancer Res., April 1, 2002; 62(7): 2162 - 2168. [Abstract] [Full Text] [PDF]
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 K. A. Furge, D. Kiewlich, P. Le, M. N. Vo, M. Faure, A. R. Howlett, K. E. Lipson, G. F. Vande Woude, and C. P. Webb Suppression of Ras-mediated tumorigenicity and metastasis through inhibition of the Met receptor tyrosine kinase PNAS, September 4, 2001; (2001) 191067898. [Abstract] [Full Text] [PDF]
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M. Guba, G. Cernaianu, G. Koehl, E. K. Geissler, K.-W. Jauch, M. Anthuber, W. Falk, and M. Steinbauer A Primary Tumor Promotes Dormancy of Solitary Tumor Cells before Inhibiting Angiogenesis Cancer Res., July 1, 2001; 61(14): 5575 - 5579. [Abstract] [Full Text] [PDF]
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C. K. Donawho, M. W. Pride, and M. L. Kripke Persistence of Immunogenic Pulmonary Metastases in the Presence of Protective Anti-melanoma Immunity Cancer Res., January 1, 2001; 61(1): 215 - 221. [Abstract] [Full Text]
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C. W. Wong, A. Lee, L. Shientag, J. Yu, Y. Dong, G. Kao, A. B. Al-Mehdi, E. J. Bernhard, and R. J. Muschel Apoptosis: An Early Event in Metastatic Inefficiency Cancer Res., January 1, 2001; 61(1): 333 - 338. [Abstract] [Full Text]
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K. A. Furge, D. Kiewlich, P. Le, M. N. Vo, M. Faure, A. R. Howlett, K. E. Lipson, G. F. V. Woude, and C. P. Webb Suppression of Ras-mediated tumorigenicity and metastasis through inhibition of the Met receptor tyrosine kinase PNAS, September 11, 2001; 98(19): 10722 - 10727. [Abstract] [Full Text] [PDF]
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