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almadrubuntu 2:54pm on Saturday, September 11th, 2010 
Makes fine adjustments a snap. Upgraded from years of mousework and finally see what the big deal was! Good Control","Natural Feel I normally use a headphones when I want watch movies because I hate disturbing others when watching movies late night. So.
henke54 7:22am on Wednesday, August 25th, 2010 
Amazing Simply put, this tablet is amazing. I went from using the Intuos2 to this tablet and I was blown away. Great but... Amazon says that "This pressure-sensitive pen has the same feature set as the Cintiq Grip Pen.
ah1270 7:50pm on Wednesday, July 21st, 2010 
Wonderful blue tooth headphones for the price. Great sound quality, keeps sound out and very comfortable Last only about one year if used every day I have been using an Intuos 2 tablet for the past 8 years (yes they were sold in 2002). From experience.
vrienduinen 5:16pm on Friday, June 18th, 2010 
This device its about....10=15% better in feel than a tablet. It will not solve your inability to make quality marks. I have worked on wacom tablets for 10+ years, worked in design for 13+, doing autonmotive and toy design.
piro 11:39pm on Monday, May 10th, 2010 
This is my first Wacom. It is much nicer than my off-market tablet, and rightfully so, but I suppose I expected more luxury out of the price.
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I love the pen pad the size takes abit of getting used as I used the extra large size at work for several years but the medium is the perfect size for...
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Documents

doc0

BRIEF COMMUNICATIONS

COMMUNICATIONS BREVES

Intestinal adenocarcinomas in two beluga whales (Delphinapterus leucas) from the estuary of the St. Lawrence River
Daniel Martineau, Stephane Lair, Sylvain De Guise, Pierre Beland
Epithelial cancer of the small intestine (ECSI) is rare in man and in all domestic animals, except sheep and cattle in certain parts of the world. We report 2 cases of ECSI affecting the proximal intestines of 2 beluga whales from a population inhabiting the estuary of the St. Lawrence River. This small, isolated group is estimated at 500 animals and is listed as an endangered population (1). Case 1 (DL-2-93) was an adult male found stranded at Ruisseau-Castor (lat 49 1'N, long 6620'W) and brought to the Faculte de medecine veterinaire, Universite de Montreal, for postmortem examination on May 21, 1993. The abdominal cavity contained 20 L of a redbrown aqueous fluid. Seven meters distal to the stomachs, the intestine was constricted by a poorly demarcated multinodular annular mass (40 cm long X 10 cm wide), extending into the thickened mesentery. The lumen of the intestine was decreased from 6 cm to 2 cm. In the strictured segment, the intestinal wall, normally 0.5 cm thick, was 7 cm thick and homogeneously white and very firm. Proximal to the stricture, the intestine was extremely dilated (Figure 1). Throughout the entire abdominal cavity, numerous small (0.2 to I cm in diameter), white, round, firm nodules were scattered on the mesenteric and peritoneal serosae. Microscopic examination revealed that the thickened intestinal wall consisted of small, randomly distributed, poorly formed tubules and acini lined by simple, cuboidal to low columnar epithelium, which was well differentiated and displayed a moderate number of mitoses (2 to 3 per 400X field). The lumen of these glandular structures contained small amounts of mucicarmine-positive material, within which were admixed

Can Vet

Figure 1. Intestinal adeiiocarcinoma in a beluga whale. Severe constriction of proximal intestine caused by the tumor is accompanied by marked dilation of the intestinal segment proximal to the constriction. Artefactual postmortem perforations of the intestine are present. The 2 arrows bracket the intestinal segment constricted by the tumor.

J 1995; 36: 563-565

Canadian Cooperative Wildlife Health Centre, Departement de pathologie et microbiologie, Faculte de medecine veterinaire, Universite de Montreal, Saint-Hyacinthe (Quebec) J2S 7C6 (Martineau, Lair); Universite du Quebec a Montreal, C.P. 8888, Succ. A, Montreal (Quebec) H3C 3P8 (De Guise); St. Lawrence National Institute of Ecotoxicology, 460, du Champ-de-Mars, suite 504, Montreal (Quebec) H2Y 1B4 (Beland). This work was supported by the Canadian Cooperative Wildlife Health Centre, Fisheries and Oceans Canada (Action Plan 2000), and the World Society for the Protection of Animals (Canada). Can Vet J Volume 36, September 1995
several necrotic epithelial cells. Beneath the mucosa, these structures were separated by an abundant fibrous stroma, replaced the normal architecture of the submucosa, and infiltrated the deeper parts of the tunica muscularis (Figure 2). The intestinal serosa was markedly edematous. The peritoneal and mesenteric nodules had a composition similar to that of the thickened intestinal wall, except that mucin was less abundant, ill-formed glandular structures were more numerous, and tumor cells were more pleomorphic and often piled up in a disorderly manner. Accordingly, this neoplasm and the accompanying nodules were designated as a scirrhous annular stenosing intestinal adenocarcinoma with peritoneal and mesenteric carcinomatosis. Case 2 (DL-2-94) was also an adult male. The animal was found stranded at Baie des Sables (lat 4843'N, long 675 1'W) and was necropsied on May 29, 1994. An intestinal stricture was found about 7.5 m distal to the pylorus. The intestinal lumen was severely reduced to less than 1 cm. The intestinal wall was 3 cm thick and the proximal intestinal segment was moderately dilated. The serosa covering the stricture was haemorrhagic. 563
Table 1. Frequency of intestinal cancer of epithelial origin in stranded beluga whales
from the estuary of the St. Lawrence River (1983-1993) compared with that in man and domestic animals

CARc of intestinal

epithelial Speciesa Beluga (3 cases) Beluga (4 cases)

Man Cattle

cancers
Small 0.8 1.85 (2.78b) 2.67 (6.87b) 10.8 (26b) 0 up to 2000

ND ND 28.5.7 3.17

Cat Horse

1.28 ND

aman (6), cattle, dog, cat, horse (7), sheep (8) bsum of epithelial cancers listed under "Intestine-NOS (not otherwise specified)" and those listed under "Small Intestine" (7) CCAR: crude annual rate per animals e.g.,

.~ ~ ~ ~ ~ ~ 7

3/4 animals with ECSI X animals = 55/73 animals 11 years X 500 animals
ECSI: epithelial cancer of the small intestine ND: not determined

3"A

,.''-'
estuary population (2), have been reported in cetaceans. One (DL-7-89) was located close to the stomachs, and
the second (DL-8-89) was 5.5 m from the anus. Thus, all but 1 intestinal cancer have been observed close to the stomachs. In cetaceans, there is no grossly detectable demarcation between the small and large intestine (3). Kleinenberg et al (3) state that the large intestine forms "about one-third of the intestines," using rather vague Figure 2. a) Intestinal adenocarcinoma in a beluga whale. criteria. Simpson et al (4) reported that the colons of Cystic cavities lined by a simple columnar epithelium are some odontocetes that they had studied were 30 cm scattered between intact muscle bundles of the tunica mus- long. Thus, we conclude that 3 and possibly 4 epithelial cularis layer. Bar = 500 ,um. HPS. b) Higher magnification. intestinal cancers reported in the beluga whale populaBar = 50 ,um. HPS. tion in the St. Lawrence River affected the small intestine. With this report, a total of 77 tumors have been Histological features of the tumor were similar to those reported in cetaceans worldwide. Of these, 30 cases of DL-2-93. (39%) come from the beluga whale population in the Complete postmortem examination of both animals did St. Lawrence River (2). not reveal any other significant lesions. Paraffin embedWe compared the estimated rate of ECSI seen in ded tissues and histological sections of both animals have that population with that seen in other animals and in been deposited in the Registry of Comparative Pathology, man, using the crude annual rate (CAR) for cancer per Armed Forces Institute of Pathology, Washington, DC, 100000 animals as described elsewhere (5) (Table 1). USA; the accession numbers are 2464200 (DL-2-93) and Stranded carcasses are rarely reported in winter (January 2464226 (DL-2-94). to March) because of the ice cover and the harsh climatic The condition index, defined as the percentage of conditions, thus the estimated CAR is a minimum figure. total body weight accounted for by the combined weights The resulting CAR is 2 orders of magnitude higher of the skin and blubber, was 46.2% for DL-2-93 and than that of man and much higher than that of domestic 45.2% for DL-2-94. These measurements were slightly animals examined at veterinary colleges (Table 1). The greater than the mean, 42.6%, calculated for the 24 other prevalence of cancer among domestic animals is probbeluga whales examined in our laboratory between ably overestimated, because 1) it includes a higher 1988 and 1990 (2). Thus, these 2 animals were not number of sick animals and 2) it consists of animals that emaciated. Muscular mass and tissue lipids may have generally live longer than wild animals (9). been depleted, however, but these parameters were not The precise etiology for ECSI has not been determined determined. in either man or animals. A viral etiology cannot be ruled To our knowledge, only 2 intestinal epithelial cancers, out, but it is unlikely, since viruses have not been incrimboth found in beluga whales from the St. Lawrence inated in the etiology of intestinal adenocarcinomas.

'. #..

Can Vet J Volume 36, September 1995
Various forms of cancers are inherited (10). Since a recent study suggests that beluga whales in the St. Lawrence River have a reduced genetic variability, when compared with that of whales from the delta of the Mackenzie River ( 1), genetic susceptibility to cancer might play a role in carcinogenesis. It appears unlikely that intestinal cancer is a feature of beluga whales, since cancers have not been reported in other populations of this species. Old age could be another cause of a high cancer rate. However, beluga whales in the St. Lawrence River appear to be younger than Alaskan beluga whales (12) (unpublished observations). In contrast to its rarity in other animals, ECSI is common in sheep from New Zealand, where it is believed to be caused by chemical contaminants (8). A high prevalence of ECSI, associated with ingestion of bracken fern and infection with papillomaviruses, has also been observed in cattle from northern England and Scotland (13). Since beluga whales in the St. Lawrence River are exposed to environmental carcinogens and immunosuppressive compounds (14), environmental contamination may have contributed, with or without other factors, to the etiology of the 4 intestinal cancers reported in this population over cvi the last I I y.

References

1. Sergeant DE. Present status of white whales in the St. Lawrence Estuary. Natl Can Rev Ecol Syst 1986; 113: 61-81. 2. De Guise S. Lagace A, Beland P. Tumors in twenty-four St. Lawrence beluga whales (Delphinapterus leucas). Vet Pathol 1994; 31: 444-449.
3. Kleinenberg SE, Yablokov AV, Bel'kovich BM, Tarasevich MN. Beluga Delphinapterus leucas investigation of the species. Jerusalem: Israel Program for Scientific Translations, 1969: 80-106. 4. Simpson JG, Gardner MB. Comparative microscopic anatomy of selected marine mammals. In: Ridgway SH, ed. Mammals of the Sea: Biology and Medicine. Springfield, Illinois: Charles C Thomas, 1972: 298-418. 5. Martineau D, De Guise S, Fournier M, et al. Pathology and toxicology of beluga whales from the St. Lawrence Estuary, Quebec, Canada. Sci Total Environ 1994; 154: 201-215. 6. Anonymous. Health Reports. Supplement no. 8, vol. 3, no. 2. Cancer in Canada. 1985, 1986. Statistics Canada, Canadian Centre for Health Information, 1991. 7. Priester WA, McKay FW. The occurrence of tumors in domestic animals. National Cancer Institute. Monograph 54, Washington, DC: US Department of Health and Human Services. Public Health Service. 1980: 1-210. 8. Newell KW, Ross AD, Renner RM. Phenoxy and picolinic acid herbicides and small intestinal adenocarcinoma in sheep. Lancet 1984; 1301-1305. 9. Fowler ME. Zoo animals and wildlife. In: Theilen GH, Madewell BR, eds. Veterinary Cancer Medicine, 2nd ed. Philadelphia: Lea & Febiger, 1987: 649-662. 10. Cotran R, Kumar V, Robbins SL. Neoplasia. In: Pathologic Basis of Disease, 4th ed. Philadelphia: WB Saunders, 1989: 239-305. It. Patenaude N, White B. Genetic variation of the St. Lawrence beluga whale population assessed by DNA fingerprinting. Molec Ecol 1994; 3: 375-381. 12. Burns JJ, Seaman GA. Investigations of belukha whales in coastal waters of western and northern Alaska. II. Biology and ecology, Report of the Alaska Department of Fish & Game, Contr. NA 81 RAC 0049, 1985: 1-129. 13. Jarrett WFH, McNeil PE, Grimshaw WTR, Selman IE, McIntyre WIM. High incidence area of cattle cancer with a possible interaction between an environmental carcinogen and a papilloma virus. Nature 1978; 274: 215-217. 14. Martineau D, Lagace A, Beland P, Higgins R, Armstrong D, Shugart LR. Pathology of stranded beluga whales (Delphinapterus leucas) from the St. Lawrence Estuary, Quebec. J Comp Pathol 1988; 98: 287-311.

doc1

Fukumura et al

AJP September 1997, Vol. 151, No. 3

Table 1.

Experimental Models for Direct Observation of Tumor Microcirculation in Vivo

Animals Mouse

Tumors Various carcinomas, sarcomas, and melanomas BA 1112 sarcoma

Models (sites)

Dorsal skin chamber Dorsal skin chamber

Parameters

Qualitative observation
Vessel diameter, RBC velocity, tissue perfusion Vessel diameter, RBC velocity,

Reference

WAG inbred Rijswijk rat Hamster
New Zealand White rabbit Fisher 344 rat

A-Mel-3 melanama

VX2 carcinoma

Dorsal skin chamber

Ear chamber (granulating tissue) Dorsal skin chamber (granulating tissue) Dorsal skin chamber

SCID mouse

Fisher rat, C3H mouse, SCID mouse C3H mouse, SCID mouse Nude mouse, SCID mouse
R3230 AC mammary adenocarcinoma LS174T human colon adenocarcinoma R3230 AC, MCaIV, HGL21, U87 human glioma

Cranial window

Vascular permeability, RBC velocity, vessel diameter Vessel diameter, RBC velocity, vessel density Vessel diameter, RBC velocity, vessel density Vessel diameter, RBC velocity, vascular permeability Vessel diameter, RBC velocity, leukocyte-endothelial interactions
Vessel diameter, RBC velocity, vessel density, vascular permeability, leukocyte-endothelial interactions

capillary length

MCaIV mammary
carcinoma, HGL21 human glioma LS174T human colon adenocarcinoma
Dorsal skin chamber, cranial window
Liver metastasis model, dorsal skin chamber

This study

animal tumor models that allow the observation of tumor microcirculation directly. These models include the rabbit ear chamber3'4; mouse, hamster, and rat dorsal skin chambers5-11; and rat and mouse cranial windows (Table 1).11,12 However, most models, except for the cranial window for central nervous system tumors or metastatic brain tumors, allow tumors to grow at ectopic sites where the local environment would be different from their natural (orthotopic) sites. It is generally accepted that the host microenvironment influences tumor biology. There are discrepancies in growth rate, angiogenesis, metastatic potential and related gene expression,13.14 and the efficacy of systemic treatments between ectopic and orthotopic tumors.15'16 Liver is the most common and critical site of distant metastasis of colorectal carcinoma. Tumorigenicity and efficacy of chemotherapeutic agents in colorectal tumors are different in liver and subcutaneous sites.16'17 Thus, we hypothesize that the liver (orthotopic) versus a subcutaneous (ectopic) microenvironment would have different effects on the development and maintenance of the microcirculation of colorectal tumor. To this end, the microcirculation of LS174T, a human colon adenocarcinoma, metastasized into the mouse liver was compared with that of the host vessels and that of the same tumor grown ectopically in the dorsal skin chamber. There are only limited models/methods to study the pathophysiology of tumors grown in orthotopic sites. More specifically, there is no study reported in the literature for the direct observation of solid tumors grown in the liver. Therefore, we first developed a new method for monitoring the microcirculation of tumors grown in the liver via the combination of an experimental liver metastasis model and intravital microscopy techniques. The liver metastasis of tumors can be established via the spleen injection of tumor cells, and the experimental procedures have been described previously.18'19 Our model

can be used to study the importance of host microenvironment in tumor biology. Recently, Kitadai et al13 and Takahashi et al14 reported that various metastasis-related genes (epidermal growth factor receptor, basic fibroblast growth factor, interleukin-8, collagenase type IV, carcinoembryonic antigen, and mdr-1) were up-regulated during growth in colon cancer xenografts grown in cecum wall (orthotopic) whereas these genes in the same tumor lines grown in subcutaneous (ectopic) sites remained unchanged. Vascular endothelial growth factor/vascular permeability factor (VEGFNPF) is a potent angiogenic factor2' and contributes to the hyperpermeability of tumor vessels.21'22 Recently, we found that the expression level of VEGF/NPF mRNA was different in vivo versus in vitro.22 Here we hypothesized that the VEGF/VPF mRNA level is also affected by tissue microenvironment. To test this hypothesis, we performed Northern blot analysis of VEGFNPF mRNA extracted from the tumors grown in the liver and subcutaneously.
Materials and Methods Animals, Surgery, and Tumor Implantation
Two-month-old male nude mice (25 to 30 g) were used for liver studies. The mice were anesthetized with a subcutaneous injection of a cocktail of 90 mg of Ketamine (Parke-Davis, Morris Plains, NJ) and 9 mg of Xylazine (Fermenta, Kansas City, MO) per kg of body weight. A small incision was made at the left lateral flank, the spleen was exteriorized, and 5 x 106 LS174T tumor cells in 100 ,ul of phosphate-buffered saline were injected with a 30gauge needle into the spleen just under the capsule. The spleen was then placed back into the peritoneal cavity, and the incision was closed with metal wound clips. Four weeks after, the mice were anesthetized again and the
Microcirculation of Liver Tumor 681 AJP September 1997, Vol. 151, No. 3
abdominal wall was opened via a midline incision. If the mice did not have macroscopic tumor foci at this stage, the wound was closed with metal clips and re-examined 2 to 4 weeks later. If no tumor foci were observed at that time, the animal was sacrificed. Dorsal skin chambers were implanted in 2-month-old male severe combined immunodeficient (SCID) mice (25 to 30 g) using the procedure described previously.' 101 Two microliters of dense LS174T (a human colon adenocarcinoma) cell suspension (-2 x 105 cells) were implanted at the center of the dorsal chamber. The measurements were made at 21 to 28 days when tumors were approximately 3 x 3 mm2 in surface area.

Experimental Procedure

Tissue Preparation
The liver lobe with metastatic tumors or the normal liver lobe was gently exteriorized after the animal was anesthetized and a midline incision was made. A circular glass coverslip (11 mm diameter) was fixed by the cyanoacrylate adhesive (Krazy Glue) onto the bottom surface of the lobe, and this cover glass was fixed to the stainless steel support in a special stage with denture adhesive cream (POLI-GRIP; Figure 1). This liver support allows adjustment of the position of the top surface of the tumor or the liver. The tissue surface was adjusted to be flat and perpendicular to the objective lens. Another circular glass coverslip that was also attached to the metal ring support was gently applied onto the top surface of the tumor or normal liver tissue. A mouse bearing the dorsal skin chamber was positioned in a polycarbonate tube and the chamber was fixed on the microscope stage as described previously.1011

objctve low

cover gSla holder

-go.,--

cover gla

cover l

I_go-m
Figure 1. Schematic of the experimental setup for observation of the liver and tumor in the liver. A: Animal preparation on the special stage (top view). The liver main lobe with metastatic tumors or the normal liver lobe was gendy exteriorized and held by the liver support device. This liver support allows adjustment of the three-dimensional position and angle of top surface. B: Tissue support (side view). A circular glass coverslip was fixed by cyanoacrylate adhesive onto the bottom surface of the liver lobe, and this cover glass was fixed to the liver support with denture adhesive cream. The top tissue surface was adjusted to be flat and perpendicular to the objective lens. The circular glass coverslip, attached to the metal ring support, was gendy applied onto the top surface of the tumor or normal liver tissue.
Microcirculatory Measurements
To obtain microcirculatory parameters, randomly selected areas (three to six locations per tumor or animal) were investigated using a X20 long working distance objective and an intravital fluorescence microscope (Axioplan, Zeiss, Oberkochen, Germany) equipped with the fluorescence filter sets for fluorescein isothiocyanate (FITC) and rhodamine (Omega Optical, Brattleboro, VT), an intensified charge-coupled device (CCD) video camera (C2400-88, Hamamatsu Photonics K.K., Hamamatsu, Japan), a regular CCD video camera (AVC-D7, Sony, Tokyo, Japan), a photomultiplier (9203B, EMI, Rockaway, NJ), and a S-VHS videocassette recorder (SVO-9500MD, Sony). To visualize the vessels, 100 ,tl of FITC-dextran (molecular weight, 2 x 106, 10 mg/ml; Sigma Chemical Co., St. Louis, MO) was injected through the tail vein. During each observation period, FITC-fluorescence images were recorded for 60 seconds and the video tapes were analyzed off-line based on the following methods. The vessel diameter in microns (D) was measured using an image-shearing device (digital video image shearing monitor, model 908, IPM, San Diego, CA). The red blood cell velocity (VRBC) was measured using the four-slit ap-

paratus (Microflow System, model 208C, video photometer version, IPM) connected to a personal computer (IBM PS/2, 40SX, Computerland, Boston, MA). The mean blood flow rates of individual vessels (Q) were calculated using D and the mean VRBC (Vmean)- Q = X/4 X Vmean X D,2 where Vmean = VRBC/a (a = 1.3 for blood vessels <10 ,um; by linear interpolation, 1.3 < a < 1.6 for blood vessels between 10 and 15 ,um; and a = 1.6 for blood vessels >15 ,um).23 The vessel density, defined as the total length of vessels per unit area (cm/cm2), was analyzed using an image processing system (NIH Image V.
1.58; Macintosh llfx, Apple Computer, Cupertino, CA). To minimize heterogeneity of vascular structure, we measured the effective vascular permeability (P) as described previously.12'24 In brief, after the injection of tet-
ramethylrhodamine-labeled bovine serum albumin (RhoBSA; 10 mg/ml, 0.1 ml/25 g of body weight; Molecular Probes, Eugene, OR), the fluorescence intensity of the tumor tissue was intermittently measured for 20 minutes. The value of P was calculated as P = (1 - HT) V/S {1/(IO - /b) X dlldt + 1IK}, where / is the average fluorescence intensity of the whole image, /I is the value of / immediately after the filling of all vessels by Rho-BSA and /b is the background fluorescence intensity. The average hematocrit (HT) of tumor vessels was assumed to be equal to 19%.25 V and S are the total volume and surface area of vessels within the tissue volume covered by the surface image, respectively. The time constant of BSA plasma clearance (K) was 9.1 x 103 seconds.12 Leukocyte-endothelial interactions in tumor vessels were monitored as described previously.11 Briefly, mice were injected with a bolus (20 ,tl) of 0.1% rhodamine-6G in 0.9% saline through the tail vein and leukocytes were visualized via an intensified CCD camera and recorded on S-VHS tapes. The numbers of rolling (nr) and adhering (na) leukocytes were counted for 30 seconds along a 100-jum segment of a vessel. The total flux of cells for 30 seconds was also measured (nt). The equations for calculating the ratio of rolling cells to total flux (rolling count), the density of adhering leukocytes (density), and the shear rate for each vessel were as follows: rolling count (%) = 100 x nrlnt; density (cells/mm2) = 106 x n,I(w- x D x 100 ,um); shear rate = 8 x Vmean/D.
and photographed under a light microscope (BX40F, Olympus, Lake Success, NY).
Data Analysis and Statistics
Data from each tumor or liver acinus were averaged before further statistical analysis. The Mann Whitney U test was used to compare the differences in vascular morphology, hemodynamics, permeability, and leukocyte-endothelial interactions between normal and tumor tissues in the liver, between two sites of tumor growth, between two location categories (periphery versus center) in the tumor, and between two size categories of the liver tumor (<3 mm versus >3 mm). The difference was considered significant when the P value was less than 0.05. Data are expressed as mean SD unless specified. N, and n represent numbers of tumors or acinus, and vessels observed, respectively.

Results

There was a large variation in the number as well as the size of metastatic LS1 74T tumor nodules in the liver. Cumulative tumor take (incidence of macroscopic liver metastases) rates at 4 weeks and 8 weeks after transplantation were 52 40% and 76 29% (n = 12 separate groups), respectively. The microvasculature of LS1 74T tumor foci in the liver was tortuous and frequently branching. Some vessels showed abrupt diameter changes and formed shunts or loops similar to the same tumor grown in dorsal skin chambers10 (subcutaneous space; Figure 2A). The frequency distribution of vessel diameter of LS1 74T liver tumor was slightly shifted to smaller size compared with that in subcutaneous space (Figure 3, B and C). In normal liver (Figure 2B), sinusoid vessel diameter was mostly within a small range (5 to 10 ,um; Figure 3A). The RBC velocity was quantified in both normal liver sinusoidal and tumor microcirculations. There was a weak correlation between vessel diameter and RBC velocity in the liver (Figure 4A), whereas RBC velocities in tumor vessels were heterogeneous and not related to the diameter (Figure 4, B and C). Blood flow rate per vessel showed correlation with vessel diameter in normal liver and tumors at both sites to the same extent (Figure 5). In addition, tumor microcirculation showed spatially and temporally heterogeneous flow distribution, delayed filling of fluorescent tracer after the injection, sluggish or intermittent flow, and even stasis. Liver tumor vessels showed significantly higher vessel diameter, RBC velocity, and blood flow rate per vessel compared with normal liver sinusoidal vessels whereas vascular density in the tumor was sevenfold lower than that in the normal liver (Table 2). Vessel diameter, RBC velocity, and flow rate per vessel were comparable in tumors at the two sites (liver and subcutaneous; Figure 6). On the other hand, liver tumors had a significantly lower vessel density than tumors in the dorsal skin chamber (Figure 6). Furthermore, in the center of the tumor, the frequency distribution pattern of vessel diameter was slightly shifted to

Northern Blot Analysis

Sample preparation and the VEGFNPF mRNA measurements were performed following the protocols described previously.22 In brief, the tissue fragment was placed in 1 ml of RNA isolation reagent, TRIzol (GIBCO, Grand Island, NY) and homogenized for 15 seconds with a Polytron (PT10-35, Brinkman, Westburg, NY). The homogenate was then mixed with 0.2 ml of chloroform and centrifuged for 15 minutes at 12,000 x g (40C). The aqueous phase was transferred to a fresh tube and the total RNA was precipitated. Thirty micrograms of the total RNA was separated by electrophoresis via 1% agarose gel containing 1.7% (v/v) formaldehyde, transferred to a Gene-ScreenPlus membrane (Biotechnology System, NEM Life Science Products, Boston, MA), and hybridized with a 32P-labeled VEGF/NPF cDNA probe synthesized by polymerase chain reaction (kindly provided by Brain Seed). The hybridized filter was autoradiographed using Kodak XAR film at -800C for 16 to 18 hours. The radioactivity, which was proportional to the amount of VEGF/ VPF mRNA, was quantified using the Phospholmager (model 410A, Molecular Dynamics, Sunnyvale, CA) and

was normalized by the amount of rRNA in each sample.

Histology

Tumors grown in either liver or dorsal skin chamber were resected, fixed in 10% buffered formalin, paraffin embedded, sectioned at 4 ,tm thickness, and stained by hematoxylin and eosin (H&E). The specimen was observed
Microcirculation of Liver Tumor 683 AJP September 1997, Vol. 151, No. 3

>, 0

",,I
Figure 2. Photographs (digitized) of microvasculature of the LS174T tumor grown in the liver and normal liver as recorded during contrast-enhanced (FITC-dextran) intravital microscopy. A: LS174T tumor grown in the liver. B: Normal liver. Tumor vessels exhibit abrupt diameter changes, tortuosity, and less vessel density. In contrast, normal liver sinusoidal vessels showed homogeneous vessel diameter, stable structure, and much higher vessel density. Bar, 100
the smaller size and the vessel density was significantly lower than that in the peripheral area (close to the interface to normal liver) of the tumor (Figure 7). There was no statistically significant difference in vascular morphology or hemodynamics between smaller and larger size tumors (Table 3). However, larger tumors had a tendency of lower vessel density and higher vascular permeability (data not shown). Vascular permeability in the tumors was an order of magnitude higher than that in normal liver. In the liver tumor, vascular permeability was twofold higher than that in the subcutaneously grown tumor (Figure 6). Flux of leukocytes and shear rate of LS174T tumor vessels were comparable between two sites, liver versus subcutaneous. Leukocyte rolling in liver tumors had a lower tendency than that in subcutaneous tumors, whereas adhesion density was comparable at both sites (Table 4). In LS174T tumor in the liver, there were marked necrotic areas in the center and the glandular structures

Diameter (gim)

Figure 3. Cumulative frequency distribution of vessel diameters in normal liver and tumors. A: Normal liver (N = 22). B: LS174T tumor in the liver (N = 23). C: LS174T tumor in the dorsal skin chamber (N = 10). d, median vessel diameter.
were well preserved (Figure 8, C and D). The border of tumor and normal liver was clear, and normal parenchymal cells adjacent to the tumor were apparently compressed (Figure 8D). On the other hand, LS174T tumor

n=l 17

Io00100

*o 0.2u

U 0.10 i

C 1000'.

.00 *.

0.1 * 00

Figure 4. RBC velocities in normal liver and tumor vessels. A: Normal liver (N= 22). B: LS174T tumor in the liver (N= 23). C: LS174T tumor in the dorsal skin chamber (N= 10). O, terminal hepatic venule; 0, terminal portal venule; 0, sinusoidal vessel (capillary) in liver acinar zone 1 (upper stream); A, zone 2 (middle); 7, zone 3 (lower stream); 0, tumor vessel.

tumors.

Diameter (gm)
Figure 5. Blood flow rates in perfused microvessels of normal liver and A, normal liver (N= 22); B, LS174T tumor in the liver (N= 23); C, LS174T tumor in the dorsal skin chamber (N1= 10). O, terminal hepatic venule; O, terminal portal venule; 0, sinusoidal vessel (capillary) in liver acinar zone 1(upper stream); A, zone 2 (middle); 7, zone 3 (lower stream); 0, tumor vessel.
skin chamber showed almost no necrotic glandular structures (Figure 8, A and B). Compression of surrounding normal cells was not evident (Figure 8B).
grown in dorsal area and fewer
VEGFNPF mRNA was detectable in every LS174T tutissue sample from two different sites. However, the expression level of liver tumor was lower than that of subcutaneous tumor (Figure 9).
Microcirculation of Liver Tumor 685 AJP September 1997, Vol. 151, No. 3

Table 2.

Microcirculatory Parameters of LS174T Tumors in Different Sites and Normal Liver

Vascular density

Vascular permeability

Vessel diameter (,im)

VRBC (mm/second) 0.181 0.03 (N = 10)

Flow rate (p1/second)

(cm/cm2)

183.7 33.0 (N

(10-7cm/second) 5)

2.35 1.4 (N

LS174T, 19.7 + 3.5 (N = 10) dorsal skin

46.2 + 21 (N = 10)

chamber LS174T, liver 17.8 4.5* (N = 23) 0.22 0.07* (N = 23) 43.3 + 22* (N = 23) 106.7 + 59.5*t (N 33) 4.77 + 3.5*t (N = 11) Normal liver 7.50 + 1.2 (N = 22) 0.115 0.02 (N = 22) 4.3 + 1.9 (N = 22) 771.43 114.6 (N 22) 0.27 0.1 (N = 6)
*P < 0.05 as compared with corresponding normal liver data. tp < 0.05 as compared with corresponding value of dorsal skin chamber group.

Discussion

The vascular morphology and hemodynamic data for the normal liver was comparable to the data published in the literature,26'27 suggesting that our setup for intravital observation did not artificially interfere with the physiological parameters in the liver. Consistent with our hypothesis, the microcirculation of LS174T tumors grown in the liver was significantly different from that of the host tissue or even the same tumor grown in the dorsal skin chamber. The vessel density in the liver tumor was sevenfold lower than that in the normal liver and also significantly lower than in the same tumor grown in the subcutaneous space. Furthermore, the vessel density in the center of the liver tumor was significantly lower than that in the periphery (close to interface with normal liver). This finding is consistent with a high incidence of central necrosis in the liver tumor whereas little or no necrosis was observed in the subcutaneous tumor. Claffey et a126 reported that genetically engineered melanoma cells with VEGFNPF overexpression formed highly vascularized tumors and exhibited little

Diameter

(nmmls)) 0.3-.
necrosis, whereas the low VEGFNPF-expressing counterpart showed extensive necrosis and little vasculature. If the expression of VEGFNPF correlates with tumor anigiogenesis, one would expect lower VEGFNPF expression in liver tumor. Indeed, the VEGFNPF mRNA level in LS174T tumor metastasized to the liver was lower than that in subcutaneous tumors. Even though the mean vessel diameter and blood flow rate per individual perfused vessel in the tumor were significantly higher than that of the normal liver sinusoidal vessels, interstitial transport of molecules would take a longer time in liver tumors because of the larger diffusion distance in the interstitial space. Tumor vessels also showed a spatially and temporally heterogeneous blood supply such as sluggish and intermittent flow, stasis, and shunts. Thus, these characteristics of tumor vessels may hinder the oxygen and nutrient supply and drainage of the waste and thus result in low P02 and low pH in the tumor.29 Low P02 is known to induce transcription and

Center

Periphery

d=13.39 pm

n"97

L~~m Diameter (m,)

(mmfs)

(cmncm2)

Vessel Density

(cnicm2) Vessel Density

200150-

(cmli)

Permeabilit

7.5B-07

5E-072.5B-07

1000.150-

Figure 6. Vessel diameters, RBC velocities, vessel densities, and vascular permeability of LS174T tumors grown in two different sites. LS174T was grown in the dorsal skin chamber (N = 10 for diameter and VRBC; N = 5 for vessel density; N = 17 for permeability) or was metastasized to the liver (N = 23 for diameter and VRBC; N= 33 for vessel density; N= 11 for permeability). P < 0.05 as compared with corresponding value of skin group.
Figure 7. Microcirculatory parameters at different location of LS174T tumor in the liver. Upper panels: Cumulative frequency distribution of vessel diameters in center (N= 7, upper left) and periphery (N = 17, upper right) of the tumor. d, median vessel diameter. Lower left panel: RBC velocity in center (N = 7) and periphery (N= 17). Lower right panel: Vessel density in center (N = 19) and periphery (N = 21). *P < 0.05 as compared with corresponding value of vessel density in center.
686 Fukumura et al AJP September 1997, Vol. 151, No. 3

Table 3.

Microcirculatory Parameters in Different Size LS174T Tumors in the Liver
Tumor diameter <3 mm >3 mm

Vessel diameter

Flow rate
17.2 4.0 (N = 17) 19.8 5.7 (N = 6)

VRBC (mm/second)

0.238 + 0.07 (N = 17) 0.170 + 0.02 (N = 6)

(pl/second) 44.(N = 17)

39.(N = 6)
112.0 64.4 (N = 26) 87.04 32.5 (N = 7)
stabilization of VEGFNPF mRNA30 and thus increase the amount of the protein in tumor and surrounding host tissues.3132 Normal liver tissue surrounding tumor has very high vessel density and thus a high tissue perfusion rate compared with skin (771 cm/cm2 versus 29510 cm/ cm2). Thus, liver tumors, especially small ones, or the tumor periphery could have better oxygen supply than subcutaneous tumors. If this is the case, that might partially explain the difference in VEGFNPF expression of the two sites. However, the relative contribution of hypoxia to the expression of VEGFNPF expression in tumors is still unclear. We are currently investigating spatial and temporal correlation of P02 versus ApO2 with VEGFNPF expression, which may be necessary to address the role

hypoxia in angiogenesis.

VEGFNPF also can lead to high vascular permeability in tumors.2233 However, here we show vascular permeability to be inversely correlated with VEGFNPF mRNA level. Endothelial cells in the liver tumor originate from the sinusoidal endothelial cells, which have quite different characteristics compared with continuous microvascular endothelial cells in the subcutaneous tissue. These differences include fenestration in the endothelium and the lack of basement membrane in the liver. A large endothelial pore cutoff size is also one of the characteristics of tumor vessels.34 Thus, our data suggest that the vascular permeability depends not only on the VEGFNPF level but also on the origin of the vessels. Also, different types of endothelial cells may have a different distribution of VEGFNPF receptors, resulting in different responses to VEGFNPF stimulation. Vascular permeability in the liver tumor was 17.7-fold higher than that in the normal liver and 2-fold higher than the subcutaneous tumor. High vascular permeability and lack of a functional lymphatic system cause high interstitial fluid pressure in tumor tissue.35 Tumor interstitial fluid pressure in LS174T tumor grown in the liver is approximately 10 to 15 mm Hg (Boucher Y, Jain RK, unpublished observation) and higher than in the same tumor grown in dorsal skin chamber (5.1 0.9 mm Hg).10 Low vessel density, heterogeneous blood supply, and high interstitial pressure can create barriers to drug delivery to solid

tumors.2

Because the liver is an encapsulated organ, tumor growing in the liver also creates solid stress to both tumor and surrounding normal tissue. Liver parenchyTable 4.
mal cells near the tumor interface had a compressed shape compared with the parenchymal cells in normal liver or far from the tumor. Under the intravital microscope, these normal areas adjacent to the tumor often showed compromised hemodynamics such as intermittent or sluggish flow. The solid stress may interfere with the blood supply to the tumor and metabolism in tumor and stromal cells.36 In agreement with our previous finding,11 leukocyteendothelial interactions in LS1 74T tumor vessels were low in both sites. Furthermore, leukocyte rolling in liver tumor vessels was approximately twofold lower than in the subcutaneous tumor vessels whereas adhesion was comparable between the two sites. As leukocyte influx and shear stress were comparable in the two sites, these differences could be due to the expression of adhesion molecules, possibly P-selectin and/or E-selectin. Transforming growth factor (TGF)-f3 is a multifunctional regulator and is known to be expressed in many human tumors37 and in the stroma of the rat colon cancer metastasis to the liver.38 TGF-,B is also known to downregulate E-selectin but not ICAM-1 or VCAM-1 expression in human umbilical vein endothelial cells.3940 This TGFP-mediated mechanism might explain the difference in leukocyte-endothelial interactions, although further investigation is needed. Recently, we investigated the role of endogenous VEGFNPF on leukocyte-endothelial interaction in vivo using VEGFNPF with a keratinocyte promoter transgenic mouse (submitted for publication). Similar to our acute studies,41 we found increased leukocyte rolling and adhesion on VEGFNPF transfected mouse skin microvessels and involvement of E- and P-selectin, ICAM-1, and VCAM-1 in these processes. These findings are consistent with the correlation of VEGFNPF mRNA levels and leukocyte-endothelial interactions in two sites in the present study. Besides the difference in liver sinusoidal endothelial cell characteristics compared with continuous microvascular endothelial cells, the parenchymal host tissue may also have a significant role in the regulation of tumor microenvironment. Hepatocytes and other nonparenchymal liver cells, such as Kupffer cells and Ito cells, may have paracrine effects on tumor cells and stromal cells. Interleukin-8 expression in human melanoma cells was low when they were grown in the liver compared with the subcutaneous space.42 Several

Leukocyte-Endothelial Interactions in LS174T Tumors Grown in Two Different Sites
LS174T, dorsal skin chamber (N LS174T, liver (N = 6)
Shear rate (1/s) 52.8 6.0

48.0 9.7

WBC flux (cells/30 seconds)

11.4 9.4 10.7 6.78

Adhesion density

Rolling count (%)

21.9.6 t 8.2

(cells/mm2) 92.99.7 115

Microcirculation of Liver Tumor

.;.i." af

18SFigure 9. Northem blot analysis of VEGF/VPF mRNA in LS174T tumors in different sites. A: Autoradiography of VEGF/VPF mRNA hybridized with 32P-labeled cDNA probe. B: rRNA in same gel. Lanes 1 and 2, LS174T in the liver; lanes 3 and 4, LS174T in dorsal skin chamber.
metastasis-related genes in human colon cancer cells were up-regulated when they were grown in the cecum wall compared with the subcutaneous space.13'14 Thus, the unique local environment of host tissue may have a significant effect on the tumor growth, angioFigure 8. Histological section of LS174T tumors. A and B: H&E section of LS174T tumor grown in dorsal skin chamber (N = 3). C and D: LS174T metastasized to the liver (N = 3). A and C: Center of the tumor. B and D: Periphery of the tumor. Bar, 100 gm.
genesis, invasion, and metastasis. The new model/method described in this paper has significant implications in two areas: 1) the liver microenvironment and its effect on tumor pathophysiology in conjunction with cytokine/growth factor regulation and 2) the delivery of drugs, cells, and genes to liver tumors.
Fukumura et al AJP September 1997, Vol. 151, No. 3

Acknowledgments

We thank Drs. Makoto Suematsu and Jiro Nishida for helpful suggestions for liver observation setup, Dr. Brian Seed for help with the Northern blot analysis, Drs. Gabriel Helminger, Yves Boucher, and Robert J. Melder for their helpful comments, and Ms. Julia Kahn for preparation of dorsal skin chambers.

23. 24.

References

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