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Journal of the National Cancer Institute, Vol. 98, No. = 5, 316-325,=20 March 1, 2006
DOI: 10.1093/jnci/djj068
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ARTICLE

A Model of Human Tumor Dormancy: An Angiogenic Switch From the = Nonangiogenic Phenotype

George N. Naumov, Elise = Bender,=20 David Zurakowski, Soo-Young Kang, = David=20 Sampson, Evelyn Flynn, Randolph S.=20 Watnick, Oddbjorn Straume, Lars A.=20 Akslen, Judah Folkman, Nava Almog =

Affiliations of authors: Departments of = Surgery=20 (GNN, EB, DZ, S-YK, DS, EF, RSW, LAA, JF, NA) and Biostatistics = (DZ),=20 Vascular Biology Program (GNN, EB, S-YK, DS, RSW, LAA, JF, NA), = Children's=20 Hospital, and Harvard Medical School, Boston, MA; The Gade = Institute,=20 Section for Pathology, University of Bergen, Bergen, Norway (OS, = LAA)=20

Correspondence to: Judah Folkman, MD, = Karp Family=20 Research Laboratories 12.128, 300 Longwood Ave., Boston, MA 02115 = (e-mail:=20 judah.folkman{at}childrens.harvard.edu ).


  =20 ABSTRACT =
Top
Notes
3D"Abstract
Introduction
Methods
Results
Discussion
References
 
<= I>Background:=20 Microscopic human cancers can remain dormant for life. = Tumor=20 progression depends on sequential events, including a = switch to=20 the angiogenic phenotype, i.e., initial recruitment of = new=20 vessels. We previously demonstrated that human tumors = contain=20 tumor cell populations that are heterogeneous in angiogenic=20 activity. Here, we separated angiogenic from nonangiogenic=20 human tumor cell populations and compared their growth. = Methods: Severe combined immunodeficient (SCID) = mice=20 were inoculated with nonangiogenic human MDA-MB-436 = breast=20 adenocarcinoma, KHOS-24OS osteosarcoma, or T98G = glioblastoma=20 cells. Most of the resulting tumors remained = microscopic (<1=20 mm diameter), but some eventually became angiogenic and = enlarged and were used to isolate angiogenic tumor = cells.=20 Angiogenic and nonangiogenic tumor cells were inoculated = into=20 SCID mice, and time to the development of palpable tumors = was=20 determined. Cell proliferation was assayed in vitro by growth = curves and in vivo by staining for proliferating cell = nuclear=20 antigen or Ki67. Microscopic tumors from both tumor cell=20 populations were examined for histologic evidence of = vascular=20 development 14 days after inoculation in mice. = Expression of=20 the angiogenesis inhibitor thrombospondin-1 was = examined by=20 immunoblotting. Results: Nonangiogenic tumors of = each=20 tumor type developed palpable tumors after means of 119 = days=20 (range: 53=96185 days) for breast cancer, 238 days = (184=96291 days)=20 for osteosarcoma, and 226 days (150=96301 days) for = glioblastoma.=20 Angiogenic cells developed palpable tumors within 20 = days after=20 inoculation. However, nonangiogenic and angiogenic = cells of=20 each tumor type had similar proliferation rates. = Fourteen days=20 after tumor cell inoculation, tumors from angiogenic = cells=20 showed evidence of functional vasculature. In contrast, = nonangiogenic tumors remained microscopic in size with = absent=20 or nonfunctional vasculature. Thrombospondin-1 = expression was=20 statistically significantly lower (by five- to 23-fold, = depending on tumor type) in angiogenic than = nonangiogenic=20 cells. Conclusions: This model provides a = conceptual=20 framework and a reproducible in vivo system to study = unresolved=20 central questions in cancer biology regarding the = initiation,=20 reversibility, and molecular regulation of the timing = of the=20 angiogenic switch.


  =20 INTRODUCTION =
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Notes
Abstract
3D"Introduction
Methods
Results
Discussion
References
 
M= ultiple=20 events are involved in cancer progression. One such = event is=20 angiogenesis; it is well established that tumor growth = beyond=20 the size of 1=962 mm is angiogenesis dependent (1=964).=20 Autopsy studies in individuals who died of trauma without=20 having had cancer diagnosed in their lifetime have = shown a high=20 frequency of microscopic cancers in various organs, = e.g.,=20 breast, prostate, and thyroid (5,6).=20 Only a small proportion (<0.5%) of such lesions will = eventually present as clinical cancers (2,6,7).=20 One possible explanation for these observations is that = most=20 human tumors arise in the absence of angiogenic activity = and=20 exist in a microscopic dormant state for months to years=20 without neovascularization. We have proposed (2,4)=20 that diagnosed tumors are those that have switched to = the=20 angiogenic phenotype, i.e., that have initiated = recruitment of=20 new vessels. Once a tumor has undergone surgical = treatment or=20 other forms of therapy, local or metastatic recurrences = may=20 also be attributed to the switch to the angiogenic = phenotype in=20 otherwise microscopic dormant tumors (8=9613).=20 Despite the clinical importance of this phenomenon, the = biology=20 of tumor dormancy is poorly understood.

Several animal models have been developed to study tumor = dormancy.=20 Hanahan et al. (14)=20 described a spontaneous tumor model (RIP1-Tag2) in = transgenic=20 mice, in which autochthonous tumors arise in the = pancreatic=20 islets as a result of the expression of the simian = virus 40 T=20 antigen (Tag) oncogene. In this model, only 4% of = tumors are=20 angiogenic, i.e., contain evidence of neovascularization, = after=20 13 weeks, whereas the remaining 96% remain microscopic = and=20 nonangiogenic (15,16).=20 The spontaneous progression of nonangiogenic lesions to = the=20 angiogenic phenotype in these tumor-bearing mice was = termed the=20 "angiogenic switch."

The angiogenic switch has also been documented in human = tumors.=20 For example, we have shown that human cancers contain=20 subpopulations of tumor cells that differ in their = angiogenic=20 potential (17).=20 Transfection of nonangiogenic human tumor cells with an=20 activated Ras oncogene resulted in their switch to the=20 angiogenic phenotype in a mouse model of human = osteosarcoma=20 dormancy (18).=20 In these previous animal models of human tumor = dormancy, the=20 angiogenic and nonangiogenic tumor cell populations = were=20 derived from either single-cell clones or from = genetically=20 modified tumor cells [i.e., Ras-transfected dormant = cells=20 (17=9619)].=20

To better understand the pathogenesis and timing of the = angiogenic=20 switch in human tumors, we developed a novel approach in = which=20 we created separate populations of nonangiogenic and = angiogenic=20 tumor cells in vivo without using molecular alterations. = We=20 used this approach to study three different human cancer = types=20 in severe combined immunodeficient (SCID) mice: breast = cancer,=20 osteosarcoma, and glioblastoma. For angiogenic and=20 nonangiogenic populations of each tumor type, we = compared=20 proliferation rates in vitro and in vivo and determined = ratios=20 of proliferation to apoptosis. The angiogenic switch in = vivo=20 was characterized by examining changes in the = vasculature.=20


  =20 METHODS =
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Notes
Abstract
Introduction
3D"Methods
Results
Discussion
References
 
<= STRONG>Establishment=20 of Nonangiogenic and Angiogenic Human Cancer Cell Lines

Human breast adenocarcinoma (MDA-MB-436), osteosarcoma=20 (KHOS-24OS), glioblastoma (T98G), and human embryonic = kidney=20 (293T) cell lines were obtained from the American Type = Culture=20 Collection (ATCC, Manassas,VA) and confirmed to be free = of=20 mycoplasma. The breast carcinoma, osteosarcoma, and=20 glioblastoma cell lines were defined as nonangiogenic = based on:=20 1) the absence of angiogenic activity, as evidenced by=20 repulsion of existing blood vessels and/or absence of=20 microvessels within the tumor; 2) their growth to only=20 approximately 1 mm in diameter or less in vivo, at which = time=20 further expansion stopped; 3) the apparent absence of "tumor=20 take" for at least 130=96238 days, until the emergence = of=20 the angiogenic phenotype; and 4) the fact that the tumors=20 remained harmless to the host until they switched to = the=20 angiogenic phenotype.

In mice injected with nonangiogenic human tumor cells = (i.e.,=20 the cell lines as originally obtained from ATCC), = occasional=20 tumors grew for each of the three cancer types following a=20 prolonged dormancy period. These vascularized tumors = were=20 removed under sterile conditions, and tumor cell lines = were=20 established from them using standard tissue culture = techniques.=20 The cell lines derived from the nonangiogenic (i.e., = dormant)=20 tumors that had switched to the angiogenic phenotype = were=20 called "angiogenic" because they produced large = angiogenic=20 tumors (up to 2000 mm3) within 1 month of = their=20 subsequent inoculation into mice. For breast cancer, a = single=20 cell=96derived clone, designated clone A1, was also = isolated from=20 the angiogenic subpopulation. This clone formed = occasional=20 angiogenic tumors following a prolonged dormancy = period.=20

All cell lines were maintained in tissue culture (37 =B0C, = 5%=20 CO2, humidified atmosphere). Breast cancer MDA-MB-436=20 cells were maintained in Dulbecco's modified Eagle = medium=20 (DMEM; Invitrogen, Carlsbad, CA) supplemented with 10% = fetal=20 bovine serum (FBS; Invitrogen). Osteosarcoma KHOS-24OS = cells=20 were maintained in Minimum Essential Medium (MEM; = Invitrogen)=20 supplemented with 10% FBS and 0.1 mM nonessential amino = acids.=20 Brain tumor T98G cells were maintained in MEM = supplemented with=20 10% FBS, 0.1 mM nonessential amino acids, and 1 mM = sodium=20 pyruvate. For in vivo experiments, subconfluent = monolayers of=20 tumor cells were harvested by trypsinization and = resuspended in=20 DMEM to a final concentration of 2.5 x 107 cells/mL. =

In Vitro Tumor Cell Proliferation

In vitro growth curves were generated by plating 5 x 104 cells in = 60-mm=20 dishes in triplicate. The cells were counted daily over = a 7-day=20 period. In an additional experiment, cells were = collected=20 during the exponential growth phase for subsequent = histologic=20 characterization (staining for Ki67).

Anchorage-Independent Growth In Vitro

For all three cancer types, the ability of nonangiogenic = and=20 angiogenic cells to undergo anchorage-independent growth = was=20 compared. In brief, 104 cells were suspended in 5 = mL of=20 0.4% agar and plated in triplicate on 10-cm plates that = had=20 been precoated with 4 mL of 0.6% agar. An immortalized = and=20 transformed human kidney cell line (293T) was used as a = positive control. Plates were monitored every other = day, and=20 when colonies became evident (after 3 weeks), plates = were=20 incubated for 8 hours with 2 mL of thiazolyl blue = tetrazolium=20 bromide (MTT) (Sigma, St. Louis, MO) to visualize = viable cell=20 colonies. The number of colonies was then counted from = 10=20 digital images of random high-power fields for each = plate.=20

Subcutaneous Tumor Growth

SCID male mice aged 6=968 weeks (Massachusetts General = Hospital,=20 Boston) were used for in vivo studies and were cared for = in=20 accordance with the standards of the Institutional Animal = Care=20 and Use Committee (IACUC) under a protocol approved by the=20 Animal Care and Use Committee of the Children's = Hospital=20 Boston. Mice were anesthetized using a 2% isoflurane = (Baxter,=20 Deerfield, IL) inhalation oxygen mixture. Suspensions = of 5=20 x 106 human = breast=20 cancer (MDA-MB-436), osteosarcoma (KHOS-24OS), or = glioblastoma=20 (T98G) cells in 0.2 mL of DMEM were then inoculated=20 subcutaneously into the lower-right quadrant of the = flank of=20 each mouse. For in vivo characterization of the = dormancy=20 period, we inoculated mice as follows: 21 mice were = inoculated=20 with nonangiogenic breast cancer cells, 11 mice with = angiogenic=20 breast cancer cells, and 12 mice with nonangiogenic = clone A1=20 tumor cells; 18 mice with nonangiogenic osteosarcoma = cells and=20 11 mice with angiogenic osteosarcoma cells; five mice = with=20 nonangiogenic glioblastoma cells and five mice with = angiogenic=20 glioblastoma cells. Mice were monitored every other day = for=20 palpable tumors at the site of tumor cell inoculation. = Tumors=20 could be detected by palpation in these shaved SCID = mice once=20 the tumors reached approximately 50 mm3. = Once tumors=20 became palpable, tumor size was measured twice a week. = Mice=20 were killed by cervical dislocation when the tumor size = reached=20 approximately 1200 mm3. To assess tumor = growth=20 kinetics, tumors were measured from the time that they = were=20 first palpable until they reached 500 mm3. Mice that = did=20 not form palpable tumors were monitored for tumor growth = for=20 up to 350 days after tumor cell inoculation. The number = and=20 proportion of angiogenic tumors that had switched from = dormancy=20 was compared between all three cancer types at day 160 = after=20 tumor cell inoculation. Representative mice were killed at=20 various time points for histology of microscopic and=20 macroscopic tumors (for example, at 14, 47, and 77 days = after=20 tumor cell inoculation).

Additional mice were inoculated with 5 x 106 MDA-MB-436 = breast=20 cancer cells for morphologic and histologic analysis as=20 follows: 25 mice were inoculated with angiogenic, 30 = mice with=20 nonangiogenic, and 30 mice with nonangiogenic clone A1 = breast=20 cancer cells. Tumor cell proliferation and apoptosis = were=20 analyzed at the following intervals: 4=967 days (10 = mice) and=20 29=9640 days (10 mice) after inoculation with = angiogenic tumor=20 cells; 4=9614 days (15 mice) and 40=9670 days (10 mice) = after=20 inoculation with nonangiogenic tumor cells, and 4=9615 = days=20 (15 mice) and 40=9670 days (10 mice) after inoculation = with=20 nonangiogenic clone A1 breast cancer cells.

Histology and Immunohistochemistry

Tumor tissue was excised from mice killed by cervical = dislocation,=20 rinsed in ice-cold phosphate-buffered saline (PBS), fixed = in=20 4% paraformaldehyde, and embedded in paraffin. = Representative=20 4-=B5m tumor cross-sections were cut from = paraffin-embedded=20 tissue, and sets of four adjacent sections were stained as=20 follows: 1) To identify proliferating cells, section 1 = was=20 stained with a 1 : 150 dilution of PC10 monoclonal = antibody=20 (DAKO, Carpinteria, CA) against proliferating cell = nuclear=20 antigen or with a 1 : 50 dilution of the monoclonal = antibody=20 against Ki-67 (M7240, clone MIB-1; DakoCytomation, = Copenhagen,=20 Denmark) after antigen retrieval for 20 minutes in = citrate=20 buffer in a microwave at 500 W; 2) To evaluate tissue = quality=20 and tumor morphology, section 2 was stained with = hematoxylin=20 and eosin; 3) To assess fragmented DNA, section 3 was = labeled=20 by the terminal deoxynucleotidyl transferase = biotin=96dUTP=20 nick-end labeling (TUNEL) technique (ApopTag kit, = Intergen,=20 Purchase, NY) according to the method of Gavrielli et = al.=20 (20);=20 4) To identify endothelial cells, section 4 was stained = with a=20 1 : 250 dilution of anti-CD31 antibody (Pecam; BD = Biosciences,=20 San Diego, CA) after antigen retrieval by Proteinase K=20 treatment. Necrotic areas were avoided for all = histologic=20 analyses.

In Vivo Permeability Assay

A modified Miles assay (21)=20 was performed to investigate differences in vascular=20 permeability in size-matched nonangiogenic and angiogenic=20 tumors. Five mice per group were inoculated with 5 x 106 angiogenic,=20 nonangiogenic, or nonangiogenic clone A1 human breast = cancer=20 cells. The modified Miles assay was performed at day 14 = after=20 tumor cell inoculation. Mice were anesthetized by=20 intraperitoneal injection of Avertin (150 mg/kg of body = weight)=20 and were then inoculated intravenously with filtered = Evans blue=20 solution (100 =B5L of 1% in PBS per mouse), which was = allowed to=20 circulate systemically for 30 minutes while the mice = were=20 maintained at 30 =B0C. All mice were then perfused = systemically=20 with PBS (pH 7.4) for 3 minutes at a pressure of 120 mm = Hg from=20 an 18-gauge cannula that was inserted into the aorta = via an=20 incision in the left ventricle. The right atrium was = then=20 incised to create a route for the saline to escape. = Patches of=20 the dorsal skin of each mouse were harvested to permit=20 visualization of dye leakage from blood vessels to = subcutaneous=20 tumor tissues, to the skin overlying the tumor, and to = control=20 skin from the contralateral flank (this perfusion = ensured that=20 no dye remained in the vascular lumen). For each mouse, = three=20 types of tissues (tumor, overlying and control skin) = were=20 excised, weighed, and placed in 1 mL of formamide = (Sigma) for 5=20 days at room temperature to extract all dye from the = tissues.=20 The extracted dye was quantified by measuring optical = density=20 at 620 nm of the formamide at the end of the 5-day = incubation.=20 All optical densitometry values were normalized to = tumor (or=20 skin) tissue weight.

ELISA Quantification of Secreted VEGF165, = bFGF, and=20 Thrombospondin-1

Nonangiogenic and angiogenic tumor cells from each of the = three=20 cancer types were plated in triplicate (5 x 106 cells/15 cm = plate)=20 in 15 mL of DMEM supplemented with 10% FBS. After 24 = hours, the=20 medium was replaced with 15 mL of serum-free medium. = The medium=20 was then collected, and enzyme-linked immunosorbent = assay=20 (ELISA) kits were used to determine concentrations of = human=20 vascular endothelial growth factor (VEGF165; = R&D,=20 Minneapolis, MN), basic fibroblast growth factor (bFGF;=20 R&D), and thrombospondin-1 (CYT Immune Science, = College=20 Park, MD) according to the manufacturers' protocols. = For each=20 sample, blank values (i.e., those for serum-free media) = were=20 subtracted, and mean results were normalized per = 104=20 cells. This assay was performed in triplicate. =

Protein Extraction and Immunoblot Analysis

Angiogenic and nonangiogenic breast cancer cells = (MDA-MB-436)=20 were grown in 10-cm tissue culture plates in DMEM = supplemented=20 with 10% FBS. When cells reached 80% confluence, half the=20 plates were treated with the phosphoinositide 3-kinase = (PI3K)=20 inhibitor LY294002=20 (Calbiochem, San Diego, CA) at a final concentration of = 10 =B5M=20 in DMEM with 0.1% FBS for 12 hours. The remaining = plates were=20 untreated. For immunoblotting, cells were harvested by=20 mechanical scraping into 4 =B0C PBS. Cell pellets were = then lysed=20 in 50 mM Tris=96HCl (pH 7.4), 150 mM NaCl, 1% NP40, 1 = mM sodium=20 orthovanadate, 5 mM NaF, 20 mM 3Dbeta=20-glycerophosphate, and complete protease = inhibitor=20 (Roche, Indianapolis, IN). Fifty micrograms of protein = was=20 loaded in the wells of a 4%=9612% precast Bis=96Tris = gel (BioRad,=20 Hercules, CA). Membranes were blocked with 5% nonfat = milk and=20 incubated with primary antibodies to c-Myc (Abcam, = Cambridge,=20 UK), phospho-Myc (Cell Signaling Technology, Beverly, = MA),=20 thrombospondin-1 (LabVision, Fremont, CA), and 3Dbeta=20-actin (Abcam, Cambridge, MA). Antibody binding = was=20 detected by incubating blots with horseradish = peroxidase=96conjugated=20 secondary antibodies, either goat anti=96mouse (c-Myc,=20 thrombospondin-1, and 3Dbeta=20-actin) or goat anti=96rabbit (p-Myc) (Jackson = Immunoresearch=20 Labs, West Grove, PA). Bands were visualized with enhanced=20 chemiluminescence reagent (Pierce, Rockford, IL). =

Statistical Analysis

The time to development of a palpable tumor (i.e., after = tumor=20 cell inoculation) was used as the endpoint of the dormancy=20 period in survival analyses. For each of the three = tumor types,=20 times to palpable tumor for the angiogenic, = nonangiogenic, and=20 nonangiogenic clone A1 (breast cancer) cells were = compared=20 using the Kaplan=96Meier product limit method (22).=20 Confidence intervals around estimated survival curves = were=20 calculated using Greenwood's formula (22).=20 In a subgroup analysis, we compared time to palpation for=20 angiogenic breast carcinoma, osteosarcoma, and = glioblastoma=20 tumor cell populations. The log-rank test was used to = compare=20 the statistical significance of differences between = survival=20 curves (23).=20 For tumors that switched to the angiogenic phenotype, = we=20 compared the median times from initial tumor palpation = (i.e.,=20 from a size of approximately 50 mm3) until = the tumor=20 reached a size of 500 mm3 using the = nonparametric=20 Mann=96Whitney U test. The Student's t = test was=20 used to compare angiogenic and nonangiogenic tumor cell = lines=20 with respect to continuous data including in vitro = tumor cell=20 doubling times, anchorage-independent growth, vascular=20 permeability, and ELISA. Two-tailed P values less than = .05 were considered statistically significant. Statistical=20 analyses were performed with the SPSS package (version = 13.0=20 SPSS, Chicago, IL).


  =20 RESULTS =
Top
Notes
Abstract
Introduction
Methods
3D"Results
Discussion
References
 
<= STRONG>In=20 Vitro Growth of Nonangiogenic and Angiogenic Tumor Cells

In vitro assessment of doubling times of all three cancer = types=20 showed no statistically significant difference between the=20 nonangiogenic and angiogenic cell lines (Fig.=20 1, A=96C). During the exponential tumor cell = proliferation=20 phase, approximately 90% of both nonangiogenic and = angiogenic=20 breast cancer cells expressed comparable levels of = Ki-67=20 protein (data not shown).



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  = 		Fig. 1. In vitro = and in vivo=20 growth of nonangiogenic and angiogenic tumor cells of = three=20 cancer types. In vitro growth (panels A=96C) = and in vivo=20 subcutaneous tumor growth (D=96F) of angiogenic = (red), nonangiogenic (black), and = nonangiogenic=20 clone A1 (green) human MDA-MB-436 breast cancer = (A,=20 D), KHOS-24OS osteosarcoma (B, E), and T98G = glioblastoma (C, F) cell lines. For in vitro = growth=20 curves, each line represents a mean number of cells = from three=20 independent replicate assays with error bars = denoting=20 95% confidence intervals. For growth of subcutaneous = tumors,=20 each line represents a single mouse. Numbers of mice = were as=20 follows: angiogenic breast cancer, n =3D 7; = nonangiogenic breast=20 cancer, n =3D 5; nonangiogenic breast cancer clone A1, = n =3D 5;=20 angiogenic osteosarcoma, n =3D 6; nonangiogenic = osteosarcoma, n=20 =3D 8; angiogenic glioblastoma, n =3D 5; nonangiogenic = gliobastoma, n =3D 5. Day of tumor cell inoculation = was=20 designated as day 0. Mice inoculated with = nonangiogenic cells=20 that did not develop palpable tumors by 160 days were=20 monitored for up to 350 days. =

 = ;
We=20 then analyzed the differences in anchorage-independent growth = between nonangiogenic and angiogenic tumor cells for all = three=20 tumor types (Fig.=20 2). Both nonangiogenic and angiogenic subpopulations = of the=20 breast carcinoma, osteosarcoma, and glioblastoma formed=20 colonies 3 weeks after plating in soft agar with no=20 statistically significant differences (all = P>.05) in=20 the number of colonies formed.



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  = 		Fig. 2. = Anchorage-independent=20 in vitro growth of nonangiogenic and angiogenic cells = of three=20 cancer types. Colony formation was assessed by a = standard soft=20 agar assay. Number of colonies (in soft agar) per high = power=20 field of view (HPF) is shown for both angiogenic = (A; black=20 bars) and nonangiogenic (N; white bars) = cells of=20 MDA-MB-436 (MDA; breast cancer), KHOS-24OS (KHOS;=20 osteosarcoma), and T98G (glioblastoma). For a control, = 293T=20 cells were used. Data represent mean values with = error=20 bars denoting the upper limit of the 95% = confidence=20 intervals. =

 = ;
Subcutaneous=20 Tumor Growth

To investigate in vivo tumor growth, we inoculated mice = with=20 either angiogenic or nonangiogenic cells from each cancer = type=20 and monitored them for as long as 350 days. Additional = mice=20 were inoculated with the nonangiogenic clone A1 breast = cancer=20 cells. The number and proportion of angiogenic tumors that = had=20 switched from dormancy within a period of 160 days after = tumor=20 cell inoculation was determined for all mice. For breast=20 carcinoma, palpable tumors developed in all seven mice=20 inoculated with angiogenic cells, in four of the five = mice=20 inoculated with nonangiogenic cells, and in three of = the eight=20 mice inoculated with nonangiogenic clone A1 cells. For=20 osteosarcoma, angiogenic tumors developed in all six = mice=20 inoculated with angiogenic cells and in one of the = eight mice=20 inoculated with nonangiogenic cells. For glioblastoma,=20 angiogenic tumors developed in all five mice inoculated = with=20 angiogenic cells and in one of the five mice inoculated = with=20 nonangiogenic cells (Fig.=20 1, D=96F).

Kaplan=96Meier analysis was used to compare the time = between=20 inoculation of tumor cells and detection of palpable = tumors=20 for nonangiogenic and angiogenic cell populations of all = three=20 cancer cell lines (Fig.=20 3). This analysis accounted for those mice in which = tumor=20 cells switched to the angiogenic phenotype and formed = tumors as=20 well as those mice that remained free of palpable tumor = for a=20 prolonged time and were censored at various time points = during=20 the dormancy period for histological analysis (as = denoted by=20 tick marks along the Kaplan=96Meier curves in Fig.=20 3). The mean times between tumor cell inoculation and = the=20 development of palpable tumors (i.e., tumors of approximately = 50 mm3) were 19 days (95% confidence interval = [CI] =3D 16=20 to 22 days) in mice (n =3D 11) inoculated with = angiogenic breast=20 cancer cells, 119 days (95% CI =3D 53 to 185 days) in = mice (n =3D=20 21) inoculated with nonangiogenic cells (log-rank=20 P<.001), and 234 days (95% CI =3D 199 to 269 = days) in=20 mice (n =3D 12) inoculated with nonangiogenic clone A1 = breast=20 cancer cells (log-rank P<.001 for comparison = with=20 angiogenic cells). Mean times to develop palpable = tumors were=20 21 days (95% CI =3D 18 to 25 days) in mice (n =3D 11) = inoculated=20 with angiogenic osteosarcoma cells and 238 days (95% CI = =3D 184=20 to 291 days) for mice (n =3D 18) inoculated with = nonangiogenic=20 osteosarcoma cells (log-rank P<.001). = Finally, mean=20 times to palpable tumor were 20 days (95% CI =3D 16 to = 24 days)=20 for mice (n =3D 5) inoculated with angiogenic glioblastoma = cells=20 and 226 days (95% CI =3D 150 to 301 days) for mice (n =3D = 5)=20 inoculated with nonangiogenic glioblastoma cells (log-rank=20 P =3D .002). By contrast, comparison of time to = develop a=20 palpable tumor for angiogenic tumor cell populations of = the=20 three cancer types showed no differences (P =3D = .15).=20 Similar dormancy times were observed for the breast and = glioblastoma tumors when inoculated orthotopically in = the=20 mammary fat pad or brain (George Naumov, unpublished=20 data).



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  = 		Fig. 3. = Kaplan=96Meier analysis=20 of time from tumor cell inoculation to palpable tumor=20 detection. The persistence of mice free of palpable = tumors was=20 represented using the Kaplan=96Meier analysis. Mice = were=20 inoculated with either angiogenic or nonangiogenic = tumor cell=20 lines: (A) Breast cancer MDA-MB-436 = (angiogenic, n =3D 11=20 mice; nonangiogenic, n =3D 21; nonangiogenic clone A1, = n =3D 12).=20 (B) Osteosarcoma KHOS-24OS (angiogenic, n =3D = 11;=20 nonangiogenic, n =3D 18). (C) T98G glioblastoma = (angiogenic, n =3D 5; nonangiogenic, n =3D 5). A drop = in the curve=20 indicates the occurrence of a palpable tumor at the=20 corresponding time since tumor cell inoculation. = Tick=20 marks denote mice euthanized for histologic = analysis that=20 had not developed a palpable tumor at that time (i.e., = censored data). Log-rank tests for differences between = angiogenic and nonangiogenic cell populations yielded=20 P<.001 for breast cancer and osteosarcoma = and=20 P =3D .002 for glioblastoma. =

 = ;
To=20 determine whether tumors from nonangiogenic cells, once they=20 emerge from dormancy, have growth kinetics similar to = those=20 of tumors from angiogenic cells, we assessed the kinetics = of=20 tumor growth in mice that developed palpable tumors from = both=20 angiogenic and nonangiogenic cell lines of each cancer = type=20 (including for breast cancer, clone A1). For this = analysis,=20 we determined the time from the detection of a palpable = tumor=20 to the time tumors reached 500 mm3. For breast = cancer,=20 the median times to reach 500 mm3 were 22 = days=20 (range =3D 11=9636 days, n =3D 7) for angiogenic cell = populations and=20 38 days (range =3D 25=9651 days, n =3D 4) for = nonangiogenic cell=20 subpopulations. For osteosarcoma, median times to reach = this=20 size were 30 days (range =3D 17=9633 days, n =3D 6) and = 25 days (n =3D=20 1) for angiogenic and nonangiogenic cell = subpopulations,=20 respectively. For glioblastoma, median times were 26 = days=20 (range =3D 21=9661 days, n =3D 5) and 39 days (range = =3D 25=9643 days, n=20 =3D 2) for angiogenic and nonangiogenic cell = subpopulations,=20 respectively. There were no differences in the time to = reach=20 500 mm3 between nonangiogenic and angiogenic = subpopulations for any of the three cancer cell types,=20 indicating that, after a tumor emerged from dormancy = (i.e., in=20 mice inoculated with the nonangiogenic tumor cells), = its growth=20 rate was comparable to that of angiogenic tumors = regardless of=20 the length of the dormancy period.

Histologic Differences Between Nonangiogenic and = Angiogenic=20 Tumors

We analyzed tumors for evidence of blood vessels on day 14 = after=20 tumor cell inoculation, when mice inoculated with either = the=20 angiogenic or nonangiogenic tumor cells had only = microscopic=20 tumors (Fig.=20 4, A, C, D), and when tumors reached 1000=962000=20 mm3 (Fig.=20 4, B, E). Fig.=20 4 shows results for breast cancer cells; results = for=20 osteosarcoma and glioblastoma were similar (data not = shown). At=20 day 14 after inoculation, angiogenic tumors (i.e., = derived from=20 angiogenic cell lines), although still less than 1 mm = in=20 diameter, contained functional blood microvessels that = were=20 CD31 positive (Fig.=20 4, K) and were filled with red blood cells (Fig.=20 4, F). By contrast, at the same time point nonangiogenic=20 tumors either lacked vasculature (CD31 negative, Fig.=20 4, H, M) or contained sparse microvessels that = lacked red=20 blood cells (Fig.=20 4, I, N). At this early time point, nonangiogenic tumors=20 either appeared white or contained microvessels mainly at = the=20 periphery of the lesion by gross examination (Fig.=20 4, C, D). By contrast, all angiogenic tumors = appeared red=20 and vascularized by gross examination (Fig.=20 4, A). Histologic examination of the nonangiogenic = tumors=20 at day 14 after inoculation showed that a minority of = tumors=20 (<10%) were completely avascular with no evidence of = intratumoral endothelial cells, as demonstrated by = absence of=20 CD31 staining (Fig.=20 4, M); most tumors showed histologic evidence of=20 undeveloped (CD31 positive) microvasculature that = lacked=20 lumens, had no red blood cells (Fig.=20 4, I), and possibly contained a few blind vascular = sprouts=20 that were CD31 positive (Fig.=20 4, N). Macroscopic tumors that had spontaneously = switched=20 to the angiogenic phenotype in mice inoculated with=20 nonangiogenic tumor cells showed histologic evidence of = vessels=20 with open lumens (Fig.=20 4, O) that were filled with red blood cells (Fig.=20 4, J), similar to the microvasculature of tumors = derived=20 from angiogenic cell lines (Fig.=20 4, G, L).



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  = 		Fig. 4. Histologic = analysis=20 of tumors from nonangiogenic and angiogenic human = MDA-MB-436=20 breast cancer cells. Photomicrographs of = representative tumors=20 are shown at day 14 (panels A, C, D) and day 47 = or 77=20 (panels B, E) after inoculation for both = nonangiogenic=20 and angiogenic tumor variants (human breast cancer). = Panels=20 A and B represent microscopic and = macroscopic=20 tumors generated from angiogenic tumor cell lines,=20 respectively. Panels C and D represent=20 microscopic tumors, generated from a nonangiogenic = tumor cell=20 line, that differ in morphologic appearance. Panel = E=20 represents a macroscopic tumor, generated from a = nonangiogenic=20 cell line, that has spontaneously switched to the = angiogenic=20 phenotype from tumor dormancy. For each tumor, = representative=20 hematoxylin and eosin=96stained sections = (F=96J) and=20 CD31-stained sections (K=96O) in high power = field of=20 views (x400) are = shown. At=20 day 14 after inoculation, angiogenic tumors (although = still=20 less than 1 mm in diameter) contained functional blood = microvessels that were CD31 positive (K) and = were=20 filled with red blood cells (F). At the same = time=20 point, size-matched nonangiogenic tumors either lacked = vasculature (absence of CD31 stain [M] and red = blood=20 cells [H]) or contained microvessels (N) = that=20 were not filled with red blood cells (I). = Ratios of=20 tumor cell proliferation to apoptosis were determined = by=20 immunohistochemical staining for Ki67 and terminal=20 deoxynucleotidyl transferase biotin=96dUTP nick-end = labeling=20 (TUNEL). These ratios were statistically significantly = lower=20 for microscopic than macroscopic tumors from the = nonangiogenic=20 cell line (P =3D .002) but not for the = angiogenic line or=20 nonangiogenic clone A1. Bars represent means = based on=20 at least 10 independent mice, with upper 95% = confidence=20 intervals. =

 = ;
Next,=20 we analyzed breast tumor cell proliferation and apoptosis = to=20 determine whether tumor dormancy resulted from tumor cell=20 quiescence. Histologic studies of tumors generated from = the=20 angiogenic cell line revealed similar ratios of tumor cell=20 proliferation to apoptosis in tumors generated up to 14 = days=20 after inoculation and in tumors that had reached a size = of more=20 than 1000 mm3 (around day 40). For tumors = generated=20 from the angiogenic breast cancer cell line, the mean = ratios of=20 Ki-67 stain to TUNEL assay results, in arbitrary units, = were=20 7.6 (95% CI =3D 4.8 to 10.4) for 14-day microscopic = tumors and=20 6.3 (95% CI =3D 3.8 to 8.8) for 40-day macroscopic = tumors (not=20 statistically significantly different, P =3D = .43) (Fig.=20 4, P). Similar ratios were observed in tumors = derived from=20 the nonangiogenic clone A1 cells, both during early = dormancy=20 (4=9614 days after inoculation) and after the switch to = the=20 angiogenic phenotype, i.e., past day 70 of inoculation = (early=20 dormancy, 6.8 [95% CI =3D 4.6 to 8.9]; angiogenic, 5.8 = [95% CI =3D=20 3.8 to 7.8]; P =3D .53). However, the ratios in=20 nonangiogenic tumors during early dormancy were statistically = significantly lower than those in tumors that had switched = to=20 the angiogenic phenotype (early dormancy, 3.1 [95% CI =3D = 2.1=20 to 4.1], angiogenic, 5.6 [95% CI =3D 4.5 to 6.6]; P = =3D .002).=20 More than 50% of tumor cells were proliferative and = more than=20 10% underwent apoptosis in all microscopic and = macroscopic=20 tumors analyzed. These findings indicate that = nonangiogenic=20 tumors, even before they have switched from dormancy to = the=20 angiogenic phenotype, have high proliferation rates and = therefore are not quiescent (i.e. are not in a = G0=20 state). These results are consistent with those of = previous=20 reports (13,17,24).=20 Moreover, establishment of angiogenic and expanding = tumors=20 appeared to be independent of the tumor cell=20 proliferation/apoptosis ratio.

Vascular Integrity and Functionality

To compare vascular integrity and functionality between = angiogenic=20 and nonangiogenic tumors, we performed a modified Miles = assay.=20 Vascular permeability was assessed within size-matched=20 nonangiogenic and angiogenic tumors, as well as in the = skin=20 overlying the tumor and in control skin from the = contralateral=20 flank of the mouse (Fig.=20 5). We assessed permeability by measuring Evans = blue dye=20 that had leaked from the vasculature after removing=20 intravascular dye by systemic perfusion of the mice with = PBS=20 (Fig.=20 5, B). Both macroscopic analysis (Fig.=20 5, A) and quantification of extracted dye indicated = that=20 angiogenic tumors retained the dye, and nonangiogenic = tumors=20 remained dye free. Vascular permeability within the = skin that=20 remained in contact with the tumor was comparable to = that of=20 skin obtained from the contralateral flank of the = mouse. Thus,=20 the observed differences in vascular permeability = between=20 angiogenic and nonangiogenic tumors appeared to be localized = to=20 the neoplastic tissue and did not affect the permeability = of=20 adjacent nonneoplastic tissue (i.e., skin).



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  = 		Fig. 5. In vivo = Miles assay=20 comparing vascular permeability between tumors = generated from=20 nonangiogenic and angiogenic cell lines. Mice were = inoculated=20 with either nonangiogenic or angiogenic tumor cells. A = modified Miles assay was performed in mice bearing=20 size-matched tumors (from nonangiogenic or angiogenic = tumor=20 cells) at day 14 after inoculation. (A) Gross=20 morphology of dye-containing angiogenic and = dye-excluding=20 nonangiogenic tumors. Dashed circle indicates = the=20 location of a tumor generated from the nonangiogenic = clone A1.=20 (B) Quantification of tissue retention of the = Evans=20 blue dye (normalized to weight of the tissue samples) = showed=20 1.5- to 2.5-fold higher vascular permeability of the = dye in=20 angiogenic tumors than in nonangiogenic tumors (at = least seven=20 mice per group). Nonangiogenic tumors and mouse skin = samples=20 (tumor-overlying or normal control) had similar = permeability.=20 Data represent mean values with error bars = denoting the=20 upper limit of the 95% confidence intervals. Vascular=20 permeability between tumors from nonangiogenic and = angiogenic=20 cell lines was compared using analysis of variance = (ANOVA). =

 = ;
Differences=20 in Expression of Pro- and Antiangiogenic Proteins Between = Nonangiogenic=20 and Angiogenic Tumor Cells

Levels of bFGF and VEGF165 (both of which are=20 proangiogenic) and thrombospondin-1 (which is an = angiogenesis=20 inhibitor) secreted by tumor cells were quantified in = the media=20 of cells grown in vitro (Fig.=20 6). In all three cancer types, angiogenic tumor = cells=20 secreted much higher levels of bFGF than nonangiogenic = cells=20 (13-fold difference for breast cancer cells, 79-fold for=20 osteosarcoma, and fourfold for glioblastoma; = P<.001 for=20 all three cancer types, Student's t test). All = tumor=20 cells secreted substantial levels of = VEGF165.=20 However, whereas angiogenic osteosarcoma cells secreted = 66-fold=20 higher levels of VEGF165 than nonangiogenic = tumor=20 cells (P<.001), levels of VEGF165 secreted by = nonangiogenic and angiogenic tumor cells were similar = for both=20 breast carcinoma and glioblastoma. In all three cancer = types,=20 nonangiogenic subpopulations secreted statistically=20 significantly higher levels of thrombospondin-1 than = angiogenic=20 cells (23-fold difference for breast cancer cells, = sixfold for=20 osteosarcoma, and fivefold for glioblastoma and breast=20 carcinoma; P =3D .011, osteosarcoma and glioblastoma;=20 P<.001).



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  = 		Fig. 6. Secretion = of basic=20 fibroblast growth factor (bFGF), vascular endothelial = growth=20 factor (VEGF165), and thrombospondin-1 by=20 nonangiogenic and angiogenic tumor cells in vitro. = Tissue=20 culture medium from angiogenic (A, black bars) = and=20 nonangiogenic (N, white bars) cells was = analyzed for=20 levels of bFGF (panel A), VEGF165 = (panel=20 B), and thrombospondin-1 (panel C) using=20 enzyme-linked immunosorbent assay, for all three human = tumor=20 cell lines: MDA-MB-436 (breast cancer), KHOS-24OS=20 (osteosarcoma), and T98G (glioblastoma). All results = were=20 standardized per number of viable tumor cells at the = time of=20 the assay. Data represent mean values with error = bars=20 denoting the upper limit of the 95% confidence = intervals.=20 Statistically significantly different results between = the=20 nonangiogenic and angiogenic pairs are shown with an = asterisk=20 (*) above the bar (angiogenic versus = nonangiogenic cell=20 comparisons for bFGF, all P<.001; for VEGF = levels,=20 MDA-436, P =3D .005; KHOS, P<.001; = for Tsp-1=20 levels, MDA-MB-436, P =3D .011; KHOS-24OS and = T98G,=20 P<.001). =

 = ;
Repression=20 of Thrombospondin-1 Activity via the PI3K=96c-Myc Pathway = Correlates With=20 the Switch From Dormancy to the Angiogenic Phenotype

Because nonangiogenic cells secreted higher levels of=20 thrombospondin-1 than angiogenic cells, we hypothesized = that=20 thrombospondin-1 expression plays a role during tumor = dormancy.=20 Previous work (19)=20 in a different breast cancer cell line (MDA-MB-435) = demonstrated=20 that thrombospondin-1 expression is governed by the = PI3K=96c-Myc=20 signaling pathway. Therefore, we compared the expression = levels=20 of c-Myc, phosphorylated-Myc (p-Myc), and thrombospondin-1 = in=20 cell lysates of nonangiogenic and angiogenic tumor cells.=20 Western blot analysis showed 2.5-fold higher levels of = c-Myc=20 and p-Myc in angiogenic cells than in their = nonangiogenic=20 counterparts (Fig.=20 7, A, B). By contrast, angiogenic tumor cells contained=20 lower levels of thrombospondin-1 than nonangiogenic cells. = This=20 finding confirmed the results obtained by measuring = secreted=20 thrombospondin-1. PI3K has previously been demonstrated to=20 induce a signal transduction cascade leading to the=20 phosphorylation of c-Myc and subsequent repression of=20 thrombospondin-1 (19).=20 Therefore, we sought to determine whether this pathway was=20 active in the angiogenic cell line. We treated both = angiogenic=20 and nonangiogenic tumor cells with the PI3K inhibitor = LY294002.=20 Treatment with this compound caused thrombospondin-1 = levels=20 within angiogenic cells to increase but had no effect on = the=20 levels in nonangiogenic cells (or those in nonangiogenic = clone=20 A1 cells) (Fig.=20 7, B). Therefore, we conclude that the PI3K = signaling=20 pathway is responsible for the repression of thrombospondin-1 = and is differently regulated in angiogenic and = nonangiogenic=20 tumor cells.



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  = 		Fig. 7. = Thrombospondin-1=20 expression in nonangiogenic and angiogenic MDA-MB-436 = human=20 breast cancer cells. (A) Western blot analysis = of=20 c-Myc, thrombospondin-1 (Tsp-1), and 3Dbeta=20-actin (loading control) in angiogenic,=20 nonangiogenic, and nonangiogenic clone A1 variants of=20 MDA-MB-436 cells. (B) Upper panel is a = representative=20 immunoblot analysis of thrombospondin-1 and = phosphorylated=20 c-Myc (p-Myc) in cells treated with the = phosphoinositide=20 3-kinase inhibitor LY294002=20 (+) or left untreated (=96). Lower panel shows = thrombospondin-1=20 expression levels, normalized to total protein gel = loading as=20 quantified by staining for 3Dbeta=20-actin. =

 = ;

  =20 DISCUSSION =
Top
Notes
Abstract
Introduction
Methods
Results
3D"Discussion
References
 
T= he=20 results presented here show that the switch to the angiogenic = phenotype in human cancer cells is highly reproducible in=20 frequency and proportion of otherwise microscopic and = dormant=20 tumors. The model for human tumor dormancy that we have = developed here is novel because the angiogenic tumor = cell lines=20 had spontaneously switched from the nonangiogenic cell = lines=20 without the use of in vitro selection (by a particular = tumor=20 cell marker) or artificial genetic alterations (15,17=9619).=20 Our results suggest that the onset and extent of = angiogenesis=20 are critical determinants of tumor progression and = growth.=20 Also, our results indicate that the establishment of = angiogenic=20 and expanding tumors in vivo (i.e., the angiogenic = switch) is=20 independent of the ratio of tumor cell proliferation to = apoptosis.

Histologic examination of microscopic nonangiogenic breast = cancers=20 revealed two categories of such tumors: 1) completely = avascular=20 tumors and 2) tumors containing empty lumens, without red = blood=20 cells, which we assume represent blind sprouts. Neither=20 category of nonangiogenic tumors showed evidence of = vascular=20 permeability, most likely because of the absence of = vasculature=20 or presumably inefficient vascular sprouting. These = categories=20 are likely to represent early stages leading to the = angiogenic=20 switch. The gross difference between the nonangiogenic = tumors=20 and angiogenic tumors (i.e., white versus red tumors) = is most=20 likely due to the reactive hyperemia that accompanies = the onset=20 of blood flow after the angiogenic switch is completed = in a=20 previously hypoxic tumor.

In the experiments reported here, we used 5 x 106 tumor cells = in=20 each inoculation. We observed sparse microvessels in the=20 nonangiogenic tumors up to 40 days after inoculation. = These=20 structures did not appear to be functional microvessels, = as=20 evidenced by lack of vascular lumens and absence of red = blood=20 cells. After 40 days, these microvascular structures could = not=20 be sustained, and they disappeared until the angiogenic = switch.=20 After the completion of this study, further work (data not=20 shown) indicated that these sparse microvessels could = be=20 induced by excessive VEGF or other proangiogenic = proteins=20 carried over in the original tumor cell inoculum. = Therefore, we=20 decreased the inoculum by decrements from 5 x 106 to 500 tumor = cells.=20 We found the optimum inoculum to be 106 tumor = cells; this=20 inoculum produced nonangiogenic, microscopic, dormant = tumors=20 that were completely avascular until the time of the = angiogenic=20 switch. Therefore, in future studies, we suggest that = the model=20 we now report could be optimized by using approximately = 106 tumor cells as the initial = inoculum.

Although our findings indicate that the lack of = angiogenesis=20 is a rate-limiting step for tumor expansion in the dormant=20 state, there may also be other processes involved in = human=20 tumor dormancy, such as differentiation programs, tumor = cell=20 survival, or immune response of the host. Although the = precise=20 mechanism and timing of tumor dormancy have not yet = been=20 completely elucidated, our novel approach provides a = means to=20 determine the molecular events and sequential steps of = the=20 angiogenic switch. The kinetics of individual stages = might be=20 of substantial practical importance for identifying an = optimal=20 therapeutic window in the treatment of early = cancer.=20

In other animal models, the growth of angiogenic tumors = has=20 been associated with reduced expression of endogenous=20 angiogenesis inhibitors, such as angiostatin (24),=20 endostatin (25),=20 tumstatin (26),=20 pigment epithelium=96derived factor (27),=20 and thrombospondin-1 (28).=20 Although it is likely that other endogenous angiogenesis=20 inhibitors play a role in the switch to the angiogenic=20 phenotype for other cancer types, in these experiments = we=20 focused on the differences in thrombospondin-1 = expression=20 between nonangiogenic and angiogenic tumor cells. In = our=20 experiments, thrombospondin-1 appeared to be a major = negative=20 regulator of angiogenesis. That is, thrombospondin-1 = expression=20 had to be reduced in the angiogenic tumor cells for the = angiogenic switch to take place. This finding further=20 strengthens No=EBl Bouck's hypothesis that the onset of = tumor=20 angiogenesis is associated with a substantial decrease = in=20 thrombospondin-1 levels (29).=20 Previous reports have shown that transfection of=20 thrombospondin-1 into human breast cancer cell lines = decreased=20 angiogenesis, tumor growth, and metastasis in = immunocompromised=20 mice (19,30).=20 Immunohistochemical analysis of human breast cancer = tissue has=20 shown marked increases in levels of thrombospondin-1 = mRNA in=20 stromal cells immediately adjacent to ductal carcinomas = in situ=20 compared with normal breast tissue (31).=20 These findings raise the possibility that increased = expression=20 of thrombospondin-1 in stromal cells and cancer cells = may=20 inhibit angiogenesis induced by VEGF and bFGF.

Our dormancy model of breast cancer shows that = thrombospondin-1=20 expression is regulated by the PI3K=96c-Myc signaling = pathway.=20 This finding is consistent with those of previous reports = (19,32=9634).=20 Western blot analysis demonstrated that the angiogenic=20 MDA-MB-436 breast cancer cells expressed higher levels = of c-Myc=20 and lower levels of thrombospondin-1 than the = nonangiogenic=20 cell line or the nonangiogenic single cell=96derived = clone A1.=20 Furthermore, when the activity of PI3 kinase was = inhibited in=20 the angiogenic cells, levels of p-Myc decreased and = levels of=20 thrombospondin-1 increased compared with levels in the=20 nonangiogenic cells. We conclude that the PI3K=96c-Myc = pathway=20 plays a key role in the regulation of thrombospondin-1 = and may=20 contribute to the observed differences in growth in = vivo.=20

In our study, most of the nonangiogenic glioblastoma and=20 osteosarcoma tumors never switched to an angiogenic = phenotype=20 during the lifetimes of the mice. By contrast, most of = the=20 nonangiogenic breast tumors did undergo the angiogenic = switch.=20 Therefore, the amount of time until the angiogenic = switch=20 appears to be distinct for a given tumor type and to = differ=20 among tumor types. We speculate that most human = microscopic=20 cancers can survive for prolonged periods by keeping = the=20 balance of pro- and antiangiogenic proteins in a steady = state=20 that favors dormancy.

The human tumor dormancy model has a few limitations. One = limiting=20 factor is that experiments characterizing the timing of = the=20 angiogenic switch can be time-consuming, lasting up to 1 = year=20 or longer. Consequently, up to this point, the mechanism = of=20 the angiogenic switch is still unclear and under = investigation.=20 Nonangiogenic tumors are invisible until the angiogenic = switch,=20 unless they are imaged using luciferase or green = fluorescent=20 protein.

Our results provide the basis for further analysis of = dormant=20 nonangiogenic tumors. Among the questions that it can be = used=20 to address are the following: 1) What are the determinants = and=20 mechanism for the "clock" that governs the angiogenic = switch?=20 Why is the timing of the switch to the angiogenic = phenotype=20 so predictable for a given tumor type? For example, why do = 100%=20 of angiogenic breast cancers become palpable at a median = of=20 19 days, when less than 20% of nonangiogenic (clone A1) = breast=20 cancers switch to the angiogenic phenotype after = approximately=20 1 year? In vivo growth of these single-cell clones = demonstrates=20 heterogeneity in the dormancy clock and will be used for=20 subsequent molecular studies of this process. 2) What = is the=20 sequence of the different stages of the angiogenic = switch,=20 i.e., lumen formation, initiation of flow, and = hyperemia? 3) Is=20 the angiogenic switch reversible? Can angiogenic tumor = cells=20 revert to nonangiogenic cells? If not, why is it = possible to=20 isolate nonangiogenic tumor cells from angiogenic = tumors, such=20 as the nonangiogenic clone A1 of breast cancer? =

During the dormancy period, nonangiogenic tumors had high=20 proliferation rates and were therefore not quiescent = (i.e. were=20 not in a G0 state). Moreover, the angiogenic = switch=20 appeared to be independent of the tumor cell=20 proliferation/apoptosis ratio. Therefore, angiogenesis = and=20 proliferation/apoptosis represent different programs in = tumor=20 progression. These models can permit further studies of = the=20 angiogenic switch, especially the different stages and = timing=20 of the process. Also, this approach may be suitable for = the=20 study of sensitive angiogenesis-based biomarker assays = and=20 novel treatment strategies. We, along with others, are = currently=20 developing an angiogenesis-based panel of blood and urine=20 biomarkers that can be quantified and used to detect=20 microscopic tumors before or during the angiogenic = switch. If=20 this approach is feasible, microscopic tumors could = possibly be=20 treated years before they become symptomatic or their=20 anatomical site is detectable. The use of this animal = model has=20 taught us that in the future, it may be possible to = liberate=20 the management of cancer from dependency on anatomical=20 site.


  =20 NOTES =
Top
3D"Notes
Abstract
Introduction
Methods
Results
Discussion
References
 
<= A=20 name=3D"">We thank Amy Birsner, Nathan Liu, and = Gerd=20 Lillian Hallseth for excellent technical assistance; = Dr. Raanan=20 Berger (Dana-Farber Cancer Institute) for technical = help with=20 the in vitro anchorage-independent growth assay; Drs. = Giannoula=20 Klement and Sandra Ryeom for valuable comments; and = Kristin=20 Gullage for photography.

Supported by the Breast Cancer = Research=20 Foundation, an Innovator Award (W81XWH-04-1-0316) from = the=20 Department of Defense, and Institute of Cancer = Research/Oliver=20 R. Grace fellowship to Dr. Nava Almog. The funding = agencies did=20 not have a role in the design, conduct, and reporting = of this=20 study.

Funding to pay the Open Access = publication=20 charges for this article was provided by the Breast = Cancer=20 Research Foundation.


  =20 REFERENCES =
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Notes
Abstract
Introduction
Methods
Results
Discussion
3D"References
&nb= sp;

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Manuscript received June 20, 2005; revised December 19, 2005; = accepted=20 January 11, 2006.


This article has been cited by other = articles in=20 HighWire Press-hosted journals:

  • Narazaki, M., Tosato, G. (2006). Tumor Cell Populations = Differ in=20 Angiogenic Activity: A Model System for Spontaneous Angiogenic = Switch=20 Can Tell Us Why. J Natl Cancer Inst 98: 294-295 = [Full=20 Text]  

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