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Department of Radiation Oncology, University of Rochester Medical Center, Rochester, New York
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSStatistical AnalysisRESULTSDISCUSSIONREFERENCES |
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Radiation research has traditionally concentrated primarily on the tumor cell compartment, with much less attention paid to either the effects of radiotherapy on the endothelial cell compartment or, more recently, the pathophysiological mechanisms leading to synergistic combinations of antiangiogenic agents and radiotherapy. The effects of radiotherapy on tumor vascular growth are complex because they depend on a competing balance between angiogenic and antiangiogenic factors. In vitro studies have shown that radiotherapy can act as both angiogenic promoter and potent antiangiogenic agent. Radiotherapy can inhibit endothelial cell survival, proliferation, tube formation and invasion (3 , 8) and directly induce endothelial apoptosis (9 , 10) . Although tumor growth is initially inhibited, angiogenic growth factors are at the same time up-regulated, leading to a secondary burst in angiogenesis and tumor cell proliferation. Radiotherapy can specifically up-regulate vascular endothelial growth factor (VEGF) receptor-2 in endothelial cells (3) and VEGF in tumor cells (3 , 11) , thereby inducing endothelial proliferation, migration, and tube formation (12) . VEGF is also a known survival factor for endothelial cells, induces antiapoptotic pathways, promotes tumor regrowth, and serves as a radioprotector (3) .
Tumor oxygenation can increase or decrease following single-dose radiation (13, 14, 15) , and fractionated radiotherapy can induce similar changes, depending on the extent to which tumor reoxygenation occurs (16 , 17) . If tumors do not reoxygenate but instead become more hypoxic during therapy, both VEGF (18 , 19) and VEGF receptor (20) levels will be further up-regulated, shifting the tumor toward a more angiogenic phenotype that may be counterproductive to treatment success. Thus, tumor cells can protect their associated vasculature from radiation damage, both directly and indirectly. This protective role can possibly be countered by co-administration of angiogenesis inhibitors, but the question then arises as to whether the antiangiogenic treatments themselves will compromise conventional therapy through reductions in oxygen delivery and decreased tumor radiosensitivity.
Previous results have been inconclusive. SU6668, an inhibitor of the VEGF, platelet-derived growth factor, and fibroblast growth factor receptors, causes tumor blood flow to first decrease then increase to higher than control levels at 24 h posttherapy (21) . One interpretation of these data is that the reduction in tumor perfusion caused by SU6668 results in hypoxic stress, thereby leading to later induction of VEGF transcription. VEGF is also known to induce nitric oxide production, thus leading to increases in vascular permeability and vasodilation, which may explain why blood perfusion was transiently elevated. Surprisingly, although blood flow subsequently decreased to 75% of control, concomitant radiotherapy was still potentiated by SU6668.
It has been hypothesized that antiangiogenic agents may serve to normalize the ineffective tumor vasculature, thereby improving delivery of oxygen and drugs (22) . However, various reports have shown increases (23 , 24) , decreases (4 , 25 , 26) , or no effect at all (5) on tumor oxygenation and blood flow following such strategies. Our previous work has shown that DC101, an antibody against VEGF receptor-2, can produce significant growth inhibition in both spontaneous and transplanted murine mammary tumors (27) . Perfused vascular counts were reduced, however, ultimately leading to tumor hypoxia, necrosis, and apoptosis. Because DC101 has also been reported to potentiate radiotherapy in other preclinical models (5 , 25) , the present studies were undertaken to characterize the microregional, pathophysiological consequences of such combined therapy. A key question was whether radioresponse would be enhanced despite the observed increase in tumor hypoxia following DC101 alone.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSStatistical AnalysisRESULTSDISCUSSIONREFERENCES |
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d3/6, where d is the diameter of the leg plus tumor, as measured using calipers. Tumor volumes were corrected by subtracting the volume of the nontumor leg. Guidelines for the humane treatment of animals were followed as approved by the University Committee on Animal Resources.
DiOC7 Perfusion Marker and EF5 Hypoxic Marker
To visualize blood vessels open to flow, DiOC7, an intravascular stain that preferentially stains cells immediately adjacent to the vessels, was injected i.v. 1 min before freezing (29)
. Localized areas of tumor hypoxia were assessed in 9.0-µm frozen tumor sections by immunohistochemical identification of sites of 2-nitroimidazole metabolism (30)
. A pentafluorinated derivative of etanidazole (EF5) was injected i.v. (0.2 ml of 10 mM EF5) 1 h before tumor freezing (31)
. Regions of high EF5 metabolism were visualized using a Cy3 fluorochrome (Amersham Biosciences) conjugated to the ELK3-51 antibody, which is extremely specific for the EF5 adducts that form when the drug is incorporated by hypoxic cells (32)
. Both the EF5 (made by the National Cancer Institute) and the ELK3-51 were obtained from the University of Pennsylvania Imaging Service Center.
DC101 Administration
Anti-VEGF receptor-2 [DC101; kindly supplied by ImClone Systems (New York, NY)] was given i.p. every 3 days at 45 mg/kg, beginning at 4 days postimplantation (early initiation, tumor volume 
190 mm3 for MCa-4; 75 mm3 for MCa-35; and 100 mm3 for the extended treatment MCa-4) or 7 days postimplantation (late initiation, tumor volume 380 mm3). An equal volume of saline was administered to control mice.
Fractionated Irradiation
Irradiations were performed on nonanesthetized mice using a 137Cs source operating at 3.0 Gy/min. Mice were confined to a plastic jig with tumor-bearing legs extended through an opening in the side, allowing tumors to be locally irradiated. Total doses of either 30 or 60 Gy were administered in 5 or 10 daily fractions of 6 Gy (omitting weekends).
Immunohistochemistry and Image Acquisition
Tumor sections were imaged using a x10 objective, digitized (QImaging Retiga 1300C peltier-cooled, 12-bit digital camera), background-corrected, and image-analyzed using Image Pro software (Media Cybernetics, Silver Spring, MD; Ref. 30
). Color image montages from 16 adjacent microscope fields (encompassing a total area of 21.6 mm2) were automatically acquired and digitally combined under four different staining conditions. First, images of the DiOC7 were obtained immediately after the sections were sliced on the cryostat. After staining, the same section was returned to identical stage coordinates, and images of EF5/Cy3 and either anti-CD31 (in MCa-4 tumors) or panendothelial cell antigen (in MCa-35) were acquired (PharMingen). Finally, sections were stained and imaged for H&E. In separate frozen sections, CD31 endothelial staining was followed by apoptosis staining using a FITC terminal deoxynucleotidyltransferase-mediated nick end labeling assay (Promega), and images were acquired at x20.
Image Analysis
Zonal Hypoxia Analysis.
To quantitate microregional hypoxia as a function of distance from perfused blood vessels, zonal analysis methods were used as described in detail previously (33)
. In brief, DiOC7 (3)
images were color segmented to identify perfused blood vessels, and a "distance filter" was applied, which replaces the intensity of each pixel with an intensity proportional to the distance of that pixel from the nearest perfused vessel. This distance-filtered image was successively thresholded and binarized to select regions of the image within specific zones around perfused vessels. Finally, these binary masks were multiplied by the corresponding EF5/Cy3 images to determine the mean EF5/Cy3 intensities within each zone.
Vascular Spacing, Apoptosis, and Necrosis.
As described previously (27)
, tumor blood vessel spacing was determined using a combination of image segmentation and distance map filtering to obtain a spatial sampling of the distance map intensities, which are directly proportional to the distribution of distances to the nearest vessel. Tumor blood vessel spacing is reflective of the median distance over which oxygen and nutrients must diffuse to reach all cells of the tumor. Colocalized images of CD31 staining and apoptosis were obtained by dilating the CD31 masks by 2 µm and using a logical "AND" image arithmetic operation with the apoptosis mask to select and count either perivascular or tumor cell apoptotic events. Regions of gross necrosis were visually selected on the H&E images and outlined with the Image Pro multiple area of interest tool for determination of percent area.
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Statistical Analysis |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSStatistical AnalysisRESULTSDISCUSSIONREFERENCES |
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0.05. Slopes and intercepts of the zonal analyses were compared using multiple linear regressions on log transformed EF5 intensities. |
RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSStatistical AnalysisRESULTSDISCUSSIONREFERENCES |
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presents tumor growth curves for all experiments. Because tumor pathophysiology can vary as a function of tumor volume, growth curves were not necessarily followed to completion; instead tumors were frozen to obtain comparable tumor volumes among treatments and controls. For early initiation MCa-4 treatments, control tumors were frozen at either small (400 ± 20 mm3) or large (1050 ± 40 mm3) tumor volumes, and combination-treated tumors were frozen at 210 ± 20 mm3 and 1130 ± 100 mm3 (Fig. 1A)
. All treatments resulted in inhibition of tumor growth but with distinct differences. For radiotherapy, tumor growth was repressed to some extent, but volumes progressively increased during treatment. For DC101, tumor progression was delayed for 3 days after the first dose, but showed little or no response to the second dose at day 7. Finally, the combination treatment totally suppressed tumor growth, continuing for up to 10 days posttherapy.
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, fractionated radiotherapy alone had no significant effect and was discontinued following only three fractions, due to the large tumor volumes. DC101 delayed tumor progression for only 1 day. Again, the combination almost totally suppressed tumor growth until tumor freezing. To gauge the pathophysiological effects of extended therapy, combination therapy was also administered for 2 weeks to a third set of MCa-4 tumors (Fig. 1C)
, and again, combination treated tumors demonstrated essentially no growth. This group was further subdivided into a "drug off" group that received DC101 only during the fractionated radiotherapy and a "drug on" group that received DC101 for 10 more days following radiotherapy. Both regimens produced significant growth inhibition with no significant differences between the two.
Fig. 1D
summarizes results for the early initiation MCa-35 tumors. Although growth rates were similar between MCa-35 and MCa-4 controls, response to DC101 was less pronounced in the MCa-35, despite the smaller initial tumor volumes. Responses to radiotherapy and the combination were similar, and both markedly suppressed tumor growth for up to 7 days posttherapy.
Total and Perfused Vessel Spacing.
Total and perfused vessel spacings are summarized in Fig. 2
. For early initiation MCa-4 tumors (Fig. 2A)
, controls were frozen at small and large volumes (400 and 1050 mm3), and treated tumors were frozen at 2 days following monotherapies and at both 2 and 16 days following the combination. Compared with volume-matched controls, total vessel spacing was significantly increased only for DC101 tumors and the recovered combination group (1100 mm3), whereas perfused vessel spacing was significantly increased after all treatments. For late initiation MCa-4 (Fig. 2B)
, DC101 and the combination significantly increased both total and perfused vessel spacing at 1 d posttherapy, but at a significantly reduced level compared with early initiation (P = 0.04). In line with its minimal effects on tumor growth rate, radiotherapy had no significant effects on total or perfused vessel spacing. Following extended combination therapy (Fig. 2C)
, both total and perfused spacing were significantly increased at 7 days posttherapy with no increase in tumor volume, indicating a reduction in both total and perfused vessel densities. By 10 days posttherapy, volumes were only slightly larger, and total vessel spacing was even further increased.
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, DC101 had no effect on perfused vessel spacing, but significantly increased total vessel spacing (P < 0.001). Perfused spacing was significantly higher for both radiotherapy tumors (P = 0.04) and the combination (P < 0.001), however, by the time tumors resumed growth at day 20 posttherapy. Although perfused spacing in the combination MCa-35 tumors was much higher than in MCa-4, the somewhat later time point for the MCa-35 may have allowed these tumors to outgrow their vasculature to a somewhat greater extent.
Overall Hypoxia.
Although either DC101 or radiotherapy significantly increased overall hypoxia in early initiation MCa-4 tumors, surprisingly, the combination had no initial effect (see 200 mm3 combination tumors in Fig. 3A
). By 16 days posttherapy, however, when volumes were 1100 mm3, the combination tumors had become significantly more hypoxic. For late initiation MCa-4 tumors (Fig. 3B)
, frozen 1 day posttherapy, only DC101 significantly increased hypoxia, but no late time point was available for the combination-treated tumors. The lack of response in the late initiation radiotherapy tumors, which was also evident in the tumor growth and vessel spacing results, may relate to the fact that these tumors were likely more hypoxic to begin with than the early initiation, and therefore also more radioresistant. For the extended treatment tumors (Fig. 3C)
, overall hypoxia was unchanged at 7 days postcombination treatment but significantly increased when tumor growth resumed 3 days later (P < 0.001). For the MCa-35 tumors (Fig. 3D)
, hypoxia increased significantly following either radiotherapy or the combination, and tumors were frozen when tumor growth resumed at day 20 posttherapy.
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presents EF5/Cy3 intensities as a function of distance from the nearest blood vessel, each point corresponding to the median intensity within a specific 20-µm-wide zone. Because EF5/Cy3 intensities averaged over the first 20-µm zone are closely related to intravascular oxygen levels, hypoxia changes at these perivascular distances are reflective of alterations in oxygen delivery capacity or functionality. Thus, flatter slopes correspond to a relatively uniform distribution of oxygen, whereas steeper slopes reflect increasing oxygen diffusional limitations. Both large and small control tumors exhibited fairly flat slopes in all plots (Fig. 4, A–D)
, indicating a relatively homogeneous distribution of oxygen. Small volume controls were not substantially different from large volume, suggesting that in these cases, tumor cells have not as yet outgrown their oxygen supply. For the early initiation MCa-4 tumors (Fig. 4A)
, DC101 produced a significant increase in perivascular EF5 intensities (P = 0.007). In contrast, perivascular hypoxia in combination-treated tumors varied from roughly equivalent to controls at 2 days posttreatment to significantly more hypoxic 2 weeks later, indicating a decrease in vascular functionality with recovery from treatment. Comparing slopes, an even more striking decrease in the ability of the blood vessels to adequately supply the tumor with oxygen is apparent following either DC101 or radiotherapy alone (Fig. 4A)
. Instead of the relatively homogeneous distribution of hypoxia seen with control tumors, both monotherapies produced a substantial increase in hypoxia with increasing distance from the vessels. The curves for combination tumors, however, are quite similar to controls immediately following treatment, but markedly steeper 2 weeks later. For late initiation MCa-4 (Fig. 4B)
, only DC101 produced significant increases in both perivascular hypoxia and slope. Following extended treatment (Fig. 4C)
, curves were unchanged at 7 days posttherapy (Fig. 4C
, sml combo), but substantially higher 3 days later (Fig. 4C
, med combo), indicating a rapid decrease in vascular function.
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, DC101 curves remained fairly flat, but were shifted to slightly more hypoxic levels. For these tumors, radiotherapy and the combination were each so effective that almost 3 weeks were required before the tumors progressed to the minimal size needed for analysis. By that time, perivascular hypoxia was significantly increased, and slopes were markedly steeper for both regimens.
Percentage Necrosis.
Fig. 5
demonstrates that hypoxia does not necessarily associate with increased necrosis. Although the early combination-treated MCa-4 tumors were significantly more necrotic (P = 0.05, Fig. 5A
), neither DC101 nor radiotherapy alone had any substantial effect. In late initiation MCa-4 (Fig. 5B)
, combination treatment again resulted in significantly higher necrosis, even at fairly small volumes (P = 0.008). Following extended combination treatment, minimal necrosis was observed (Fig. 5C)
. Although percentage necrosis was fairly similar between MCa-4 and MCa-35 controls, response to combination treatment was minimal in the case of the MCa-35 (Fig. 5D)
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illustrates changes in the numbers of apoptotic tumor and endothelial cells for the early initiation MCa-4 tumors. All treatments significantly increased the numbers of apoptotic tumor cells, but the combination produced the most substantial rise. For endothelial cells, in contrast, only the combination produced a significant increase, suggesting a sensitization of the endothelial cells with this combined regimen.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSStatistical AnalysisRESULTSDISCUSSIONREFERENCES |
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In neuroblastoma xenografts, treatment with either DC101 or 6 Gy radiation led to increased tumor hypoxia, as determined polarographically (25) . Following combination treatment, hypoxia was slightly reduced, but tumors were still significantly more hypoxic than controls. Similarly, combinations of fractionated radiotherapy with either SU11248 or SU5416 served to decrease tumor blood flow (6 , 36) , and maintenance of SU11248 following combination therapy produced a clear improvement in tumor control. This contrasts with current results, in which no additional enhancement was found when tumors were maintained on DC101 following the combination, although SU11248 inhibits both VEGF receptor-2 and platelet-derived growth factor receptor, and maintenance therapy was somewhat shorter in the current study.
Combination therapy is clearly much more effective than either radiotherapy or DC101 in suppressing growth in MCa-4 tumors. For late initiation tumors, radiotherapy had almost no effect, whereas DC101 slightly slowed tumor growth. In marked contrast, the combination totally blocked tumor progression for weeks beyond completion of 1- or 2-week therapies. In MCa-35 tumors, tumors were much more sensitive to radiotherapy alone, and it was impossible to gauge whether DC101 provided additional benefit. The lack of a synergistic effect in these tumors could be related to: (a) alterations in the balance of angiogenic and antiangiogenic cytokines; (b) the increased radiosensitivity of the MCa-35; or (c) the fact that treatment was initiated at somewhat smaller tumor volumes than for the MCa-4.
Although early or late initiation monotherapy with either DC101 or radiotherapy increased both perfused vessel spacing and overall hypoxia, changes following combined therapies were somewhat more complex. Perfused vessel spacing increased, but in the absence of a corresponding increase in hypoxia. Bruns et al. (4) reported a somewhat similar phenomena, whereby hypoxia increased significantly following DC101 alone, but decreased when combined with gemcitabine. They hypothesized that the development of new blood vessels was not yet required in their smaller combination-treated tumors, because tumor cells were still within the oxygen diffusion distance of preexisting host vessels. Although overall hypoxia was unchanged in MCa-4 tumors following the combination, necrosis was significantly higher, suggesting that: (a) the ability of the vessels to supply oxygen is clearly compromised; and (b) the tumor cells become progressively more necrotic following extended hypoxia. Given the fact that growth of the combination-treated tumors was constrained to quite small tumor volumes for either early initiation, late initiation, or extended treatment regimens, the most likely reason that hypoxia does not initially increase in these tumors is that they have not as yet had a chance to outgrow their DC101-compromised vasculature, due to the additional tumor antiproliferative effects of the radiotherapy. Even at these relatively small tumor volumes, regions of hypoxia were almost exclusively limited to areas immediately adjacent to necrosis, which were also furthest from the surrounding host vasculature.
A likely mechanism for the effectiveness of the combination treatment is that DC101 serves to inhibit the ability of VEGF to act as a survival factor for endothelial cells (37) , thus sensitizing the vessels to radiation damage (6) . Although tumor cell apoptosis in MCa-4 tumors was increased by each treatment, the combination produced the most striking effects and was the only regimen that significantly increased endothelial cell apoptosis. Because perfused vessel spacing increased following the combination, with no change in tumor volume, perfused vessels were clearly eliminated during therapy. Two weeks postcombination therapy, when the tumors had substantially increased in volume, total and perfused vessel spacing as well as overall hypoxia were markedly increased. Because total and perfused perivascular hypoxia also increased, blood flow was most likely compromised in these remaining vessels. At this time, however, it cannot be conclusively stated whether: (a) total or functional vessels are destroyed by the treatment; (b) vessel growth was simply delayed allowing the tumor to outgrow the functional vasculature; or (c) some combination of the two occurred. In any case, the net result was an increase in localized islands of tumor hypoxia with accompanying necrosis following treatment recovery.
Previous work has shown increases in both tumor cell and endothelial apoptosis following DC101 alone, although following substantially longer treatment times (38) . Immature, non-pericyte-coated vessels have also been shown to be more susceptible to damage by antiangiogenic agents (39) , although it is as yet uncertain whether the same holds true following radiotherapy. Because these neovessels are probably not yet as effective in delivering blood flow and oxygen, specifically targeting them could lead to a decrease in perfused vessel density without markedly influencing functional vessel density. Furthermore, damaged immature vessels may be unable to progress to a more functional phenotype, and adjacent tumor cells would gradually outgrow their nutrient supply, ultimately leading to the observed increase in necrosis. Although oxygenation in these expanding necrotic regions would clearly be reduced, overall measurements of tumor hypoxia using EF5 binding are constrained to viable regions of the tumor, which are more relevant to radioresponse. Because overall hypoxia remained relatively constant following combination treatment, radiosensitivity would not be expected to be compromised. Recent work somewhat contradicts this mechanism as the sole determinant, however, because response to the combination of fractionated radiotherapy plus VEGF receptor-2 inhibition was most effective when delivered postirradiation (40) . Given that concomitant administration resulted in no improvement, endothelial cell radiosensitization may be a less important component of response in some tumors, although vessels damaged by irradiation could also remain sensitive to later VEGF receptor-2 inhibition (40) .
The present results also highlight the importance of tumor implantation site in evaluating tumor pathophysiological response. Compared with mammary fat-pad implantations (27) , tumor growth rates in the leg implants were 2–3-fold higher in both control and DC101-treated tumors. In the leg tumors, angiogenic vessels can presumably sprout from abundant, preexisting, host vessels that supply the leg muscle, leading to well-vascularized, oxygenated tumors. In the fat-pad, however, the host tissue is less vascularized, and the tumor is more dependent on neovessel development to supply its metabolic needs. Accordingly, MCa-4 vessel counts were much higher in the leg-implanted tumors than in the fat-pad, leading to a more uniform distribution of oxygen. In the MCa-35, in contrast, vessel counts were comparatively lower in the leg implants. In this environment, localized levels of angiogenic growth factors may be more important in promoting sufficient expansion of the tumor vasculature. Interestingly, although DC101 produced similar tumor growth inhibition at both sites, significantly more hypoxia was induced in leg implants in each tumor model. Although combination therapy had no immediate detrimental effects on tumor oxygenation, tumor necrosis was significantly increased, and tumors became substantially more hypoxic following cessation of treatment. It remains to be seen whether tumors will remain well oxygenated throughout an even more extended 6–8-week course of fractionated radiotherapy or eventually become hypoxic and whether radiotherapy fraction sizes can be further reduced in combination with DC101 while maintaining similar growth delays. Furthermore, more detailed studies are clearly warranted to address these questions as well as to optimize scheduling with antiangiogenic strategies.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Requests for reprints: Bruce M. Fenton, Box 704, University of Rochester Medical Center, Rochester, NY 14642. E-mail: bruce.fenton{at}rochester.edu
Received 2/ 9/04. Revised 6/ 8/04. Accepted 6/16/04.
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSStatistical AnalysisRESULTSDISCUSSIONREFERENCES |
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, controls; 
, radiotherapy alone; 
, DC101 alone; 
, combo, radiotherapy and DC101; and vertical dashed lines, treatment beginning and end times. A, MCa-4 tumors, early initiation treatment (begun at volumes 
) cells for the early initiation MCa-4 tumors. All tumor volumes ranged from 300–400 mm3, and treated tumors were frozen at 2 days posttherapy. *, statistically significant differences in relation to volume-matched controls; 5x6, 5 x 6 Gy radiation fractions; combo, radiotherapy and DC101.