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Stroma Formation in the Peritoneal Lining' Janicea [CANCERRESEARCH55, 376-385, January 15, 1995J Pathogenesis of Ascites Tumor Growth: Angiogenesis, Vascular Remodeling, and Stroma Formation in the Peritoneal Lining' JaniceA. Nagy,2EllenS. Morgan,KempT. Herzberg,EleanorJ. Manseau,Ann M. Dvorak,and HaroldF. Dvorak Departments of Pathology. Beth Israel Hospital and Harvard Medical School, Boston, Massachusetts 02215 ABSTRACT In the two accompanying papers (18, 19), we demonstrated that two transplantable murine ascites carcinomas, MOT and TM/St. (13—17) In the accompanying papers, we demonstrated that two murine ascites shared several important properties with these same and many other tumors (MOT and TA3/St) Induced peritoneal lining blood vessels to transplantable and autochthonous tumors growing in solid form (1—4, become hyperpermeable to plasma proteins, leading to extravasatlon of fibrinogen and Its dotting to cmss-linked fibrin in peritoneal lining tissues 7, 20—27).Shared properties included: (a) secretion by tumor cells of (peritoneal wall, mesentery, and diaphragm). In solid tumors, vascular a potent cytokine, VPF3; (b) hyperpermeabiity of tumor blood yes hyperpermeabifity and fibrin deposition lead to the generation of vascu sels; (c) extravasation of plasma proteins, including fibrinogen; and larized connective tissue. In order to determine whether fibrin had similar (d) clotting of a fraction of extravasated fibrinogen to form cross consequences in ascites tumors, the vasculature and stroma of peritoneal linked fibrin deposits in peritoneal lining tissues. lining tissues were analyzed at successive Intervals after i.p. tumor cell Whether resulting from solid tumors (4, 7, 26), wound healing injecflon In both MOT and TA3/St asdtes tumors, the size and number (21, 23), or from direct implantation of fibrin-filled porous chambers of peritoneal lining mlcrovessels increased significantly by 5-8 days. (28), deposition of fibrin in tissues has been shown to stimulate the Subsequently, peritoneal lining vessels Increased in cross-sectional area by ingrowth of new blood vessels and the subsequent development of as much as 15-fold and peritoneal vascular frequency increased by up to fibrous connective tissue stroma. The present study was undertaken to 11-fold. Incorporation of [3H]thymidine by mesenteric blood vessels was negligible In control animals but came to involve 20 and 40% of endothe determine whether fibrin deposited in the peritoneal lining tissues of Dm1cells lining mesenteric vessels in MOT and TA3/St ascites tumor ascites tumor-bearing animals also induced angiogenesis and the bearing mice, respectively. After an early dramatic Increase In cross laying down of new connective tissue stroma. sectional area, peritoneal lining microvessels subsequently underwent a novel form of remodeling to smaller average size as the result of tram vascular bridging by endothellal cell cytoplasmic processes. Thus, both of MATERIALS AND METHODS the ascites tumors Studiedhere induced anglogenesis and stroma similar to that elicited when these same tumors were grown in solid form. How Tumors. TA3/St and MOT tumor cells (1 X 10@)werepassaged weekly in ever, stroma developed more slowly In ascites than in solid tumors and the peritoneal cavities of syngeneic, 5- to 6-week-old A/Jax and C3Heb/FeJ was entirely confined to a compartment(peritoneal lining tissues) that was mice, respectively (18). Sequential study of peritoneal lining tissues was distinct from that (peritoneal cavity) containing the majority of tumor conducted through day 8 after i.p. injection of 10@TA3/Sttumor cells; most cells and ascites fluid. These findings are consistent with the hypothesis animals died by day 9 or 10. In contrast, the majority of animals injected i.p. that vascular hyperpermeability, induced In both solid and ascites tumors with 10@MOT tumor cells survived for >1 month and were followed at by tumor cell-secreted vascular permeability factor, Is a common early intervals for up to 28 days. step in tumor anglogenesis, resulting in fibrinogen extravasatlon, fibrin Vascular Mapping with Microfil. To map the microvasculature of the deposition, and likely other alterations of the extracellular matrix that tissues lining the peritoneal cavity, animals were perfused with Microfil White together stimulate new vessel and fibroblast lngrowth. (MV-112; Canton Bio-Medical products, Inc., Boulder, CO), a silicone rubber compound (27). After the Microfil had hardened, peritoneal lining tissues were dissected free, fixed in formalin, dehydrated in a sequence of ethyl alcohols, INTRODUCTION and cleared in methyl salicylate for examination in a Wild macroscope. Tissue Processing for Microscopy. Tissues lining the peritoneal cavity Experimental tumors growing in solid form commonly initiate the (peritoneal walls, diaphragm, and mesentery) were fixed and processed for generation of vascularized stroma by rendering local blood vessels 1-p.m-thick, Epon-embedded and Giemsa-stained light microscopic sections hyperpermeable to plasma proteins (1—5).As a consequence of vas (18, 27). To evaluate blood vessel size and frequency at various stages of cular hyperpermeability, plasma fibrinogen, normally confined to ascites tumor growth, 1-pm Epon sections of randomly selected portions of plasma, extravasates and clots in the extravascular space to form a mesentery were photographed at constant magnification (X675). Color prints fibrin gel; such gels provide a provisional stroma which imposes (4 x 6 inches;Ektar25; EastmanKodak)were prepared,andall microvessels structure on solid tumors and stimulates the ingrowth of new blood (defined as vessels lacking muscle in their walls) were identified, and their vessels and of fibroblasts which synthesize and deposit the matrix lumens were outlined with a photo marking pen. Individual prints were then proteins and proteoglycans of mature tumor stroma (6, 7). In contrast, imaged with a video camera into a computer equipped with IM-series version it has been thought that ascites tumors do not generate a new sup 3.46p software (Analytical Imaging Concepts). Once digitized, measurements of vessel size (diameterand cross-sectionalarea) and density (numberof porting stroma unless they implant on peritoneal surfaces; rather, vessels per unit area) were calculated. they grow as a suspension of malignant cells in a plasma exudate, Identification of Hyperpermeable Blood Vessels and Endotheilal Celia ascites fluid, that is comparable to the interstitial fluid of solid tumors That Had Incorporated [3H]Thymldlne. To identify leaky tumor blood (8-17). vessels, mice received colloidal carbon i.v. 1 h prior to harvest (18). In some experiments,animals were also injected i.v. with [3H]thymidine(25 @Ci/ Received 6/1/94; accepted 11/11/94. mouse; Du Pont New England Nuclear, Boston, MA) 2 h prior to harvest. The costs of publication of this article were defrayed in part by the payment of page Mesenteries were fixed and processed for 1-p.m Epon sections as above. Epon charges. This article must therefore be hereby marked advertisement in accordance with sections were coated with Kodak NTB-2 emulsion for autoradiography. Sec 18 U.S.C. Section 1734 solely to indicate this fact. tions from randomly selected blocks were examined in their entirety at a I This work was supported by NIH research Grants CA-40624 and CA-58845 and under terms of a contract from the National Foundation for Cancer Research and by a magnification of X1000; all blood vessels were identified, and carbon-labeled grant from the BIH Pathology Foundation, Inc. Part Three of a series on “Pathogenesisof (hyperpermeable) blood vessels and [3H]thymidine incorporating (proliferat Ascites Tumor Growth.― 2 To whom requests for reprints should be addressed, at Department of Pathology, Beth Israel Hospital, 330 Brookline Avenue, Boston, MA 02215. 3 The abbreviation used is: VPF, vascular permeability factor. 376 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1995 American Association for Cancer Research. @@ -@ @“ :@- ANGIOGENESIS/STROMAGENERATION IN ASCITES TUMORS 0 ., -. 4, @, A .@i @. S@ @@@ , ‘@S@ :;;@ @‘ .-S ,‘-@- @@-:;;@-@ @ . .‘ , @- : ‘@@‘ .5 S-@@-5 @ - 5.@, y@. ____ .--“ @ CA __ 1 @@@ !--. @S@( 5@555@-5@ @55 -- @@@ .1T@TiiiT L.. Fig. 1. Peritoneal walls ofmice bearing TA3/St (A and B)or MOT(C-F) ascites tumors. A and B, peritoneal walls of7-day TM/St ascites tumor-bearing mice exhibit micmvascular congestion, microvascular hyperpermeability (carbon leakage, arrowheads), interstitial edema (spreading apart of muscle bundles), and activation of surface mesothelial cells. C and D, peritoneal walls of 16-day MOT ascites tumor-bearing mice illustrate dramatic increase in size and number of superficial microvessels (v) E, another 16-day peritoneal wall to illustrate collagen deposition (c) between muscle bundles in space formerly occupied by fibrin deposits (Fig. 2; Ref. 19). Blood vessels (arrowheads) have reverted to smaller size. F, peritoneal wall at 27 days after i.p. injection of MOT tumor cells shows piling up of tumor cells on the peritoneal surface with superficial blood vessels (arrowheads) and underlying collagen(c)deposition.Eventhemostsuperficialbloodvessels(arrowheads)havereturnedtoa smallersize.Allare1-gunthick,Giemsa-stainedEponsections.AandB, X430(6w', 16 g@m);C,D, and F, x 270; E, X 340. ing) endothelial cell nuclei were separately counted. More than 5000 individual becoming large, thin-walled channels with persistent hyperpermeabil vessels and a somewhat larger number of endothelial
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