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Cell, Tumor, and Stem Cell Biology |
Departments of 1 Biological Regulation and 2 Veterinary Resources, Weizmann Institute, Rehovot, Israel and 3 OncoRay—Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Technical University of Dresden, Dresden, Germany
Requests for reprints: Michal Neeman, Department of Biological Regulation, Weizmann Institute, Rehovot 76100, Israel. Phone: 972-8-934-2487; Fax: 972-8-9346264; E-mail: michal.neeman{at}weizmann.ac.il.
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Introduction |
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90% of all ovarian tumors (benign and malignant; ref. 2). This surface epithelium layer participates in the ovulation process, both actively through the secretion of proteolytic enzymes and cytokines as well as mechanically as the initial site of tissue degeneration. The incidence of ovarian epithelium cancer increases with numerous ovulation events that do not lead to pregnancy. Reactive oxidants produced at the ovulation wound during ovulation promote DNA aberrations in the surface epithelium cells, which consequently become more susceptible to transformation. Hence, the "incessant ovulation" hypothesis was introduced. The theory claims that pregnancy and lactation protect against ovarian cancer, whereas repeated ovulations without long cessation periods facilitate malignancy (2, 3). Despite the link between ovulation and ovarian cancer, the prevalence and severity of the disease are highest in postmenopausal women. Thus, there seems to be a long latency period between transformation of the ovarian epithelial cells and progression of ovarian cancer. This etiology of ovarian cancer led to the "hormonal hypothesis," linking ovarian carcinoma with hormonal changes that accompany menopause and particularly implicating the gonadotropin hormones, luteinizing hormone and follicle-stimulating hormone, in tumor progression (4). We previously showed that implanted ovarian carcinoma tumors respond to gonadotropin stimulation indirectly by induction of adhesion and angiogenesis (5, 6). In the absence of these stimuli, implanted ovarian carcinoma spheroids show extended dormancy characterized by futile cycles of angiogenesis and vascular regression, which could be detected by magnetic resonance imaging (MRI; refs. 7, 8). Thus, tumor-derived vascular endothelial growth factor (VEGF) was sufficient for inducing angiogenesis but not sufficient for vascular maintenance in a manner that would support tumor growth. Exit from dormancy was marked by infiltration of stroma cells and particularly myofibroblasts, which promoted vascular stability and functionality by expression of angiopoietin-1 and angiopoietin-2 (9).
The role of fibroblasts in ovarian cancer progression is consistent with previous reports that fibroblasts have a fundamental role in pathologic circumstances such as wound healing and tumor progression (10, 11). Coinoculation of fibroblasts with tumor cells promoted tumor progression and angiogenesis in prostate cancer (12, 13), ovarian cancer (12, 14), and breast cancer (15). The tumor stroma, also referred to as "reactive stroma," is correlated with desmoplasia (i.e., increase in fibroblastic cell population, capillaries, inflammatory cells, collagen type I, and fibrin deposition; ref. 16). The desmoplastic reaction is characterized by pronounced alterations in the phenotype and expression profile of the associated fibroblastic cells (17), such as expression of 
smooth muscle actin (-SMA), which have thus have been termed as myofibroblasts (18).
Homeostasis of epithelium is achieved through balanced signaling cascades via factors that are secreted by both epithelial and stromal cells and that exert their functions through paracrine and autocrine mechanisms (11, 19). Fibroblasts are the major constituents of the connective tissue and, to a high degree, are responsible for synthesis of extracellular matrix components and formation of basement membrane. Immunohistochemistry of invasive endometrial tumors showed myofibroblast staining for growth factors related to angiogenesis and tumorigenesis (20).
Angiogenesis is a basic requirement for solid tumor growth and progression because all solid tumors, regardless of their origin, require stroma for their progression. In contrast to the normal blood vessels, tumor vessels are characteristically immature, tortuous, and chaotically scattered, forming leaky, poorly functioning endothelial channels, either devoid or loosely attached to periendothelial cells and are more dependent on VEGF for their survival (21).
Recent studies suggested that matrix-bound fibroblasts enhance angiogenesis as well as endothelial cell motility (22). Interactions between endothelial cells and fibroblasts in three-dimensional cocultures of human umbilical vein endothelial cells (HUVEC) and human primary fibroblasts revealed temporal and spatial organization, in which the endothelial cells composed the inner mass of the spheroid whereas fibroblasts were typically located at the periphery (14, 22–24). Additionally, human skin fibroblasts were recently shown to support the migration and tube formation of HUVEC in a three-dimensional culture system (25).
Recruitment of fibroblasts to tumor stroma is governed by molecular factors that are only partly known. Platelet-derived growth factor (PDGF) secreted by tumor cells can be recognized by the PDGF receptor on the mesenchymal cells and has been shown to participate in the recruitment of pericytes to maturing blood vessels (15). It is likely that myofibroblasts are recruited from different sources as cancer formation progresses (11, 26, 27). During initial tumor stages, it was suggested that myofibroblasts differentiate from the local fibroblast population in the epithelial stroma on transforming growth factor (TGFß1) stimulation, whereas at later tumor progression stages, myofibroblasts are recruited from distant locations (28–32). Green fluorescent protein–positive bone marrow–derived fibroblasts were recruited to both s.c. and i.p. tumors in mice (33). Furthermore, fibroblasts that originated from various organs such as skin, lung, and bone marrow showed different efficiencies of fibroblasts recruitment into i.p. ovarian tumors (34). In this context, myofibroblastic modulation seems to depend on complex environmental network, in which TGFß1 is significantly, but not exclusively, involved (35).
The aim of the study reported here was to track the systemic recruitment of fibroblasts into tumors by MRI/near-IR imaging. MRI has become a favorable tool for noninvasive tracking of cells (22, 36). The vast majority of cell labeling studies for MRI use superparamagnetic iron oxide particles. Labeled cells are typically detected through the large magnetic susceptibility effect, resulting in easily detectable signal void. Conversely, paramagnetic metal ions such as gadolinium (Gd3+) mainly affect T1 relaxation rate of the surrounding water, thus enhancing the MRI signal of the labeled cells in comparison with nearby tissue (37–39). Recently, MRI was applied for tracking of endothelial precursor cells (EPC) that are involved in tumor angiogenesis and vascular remodeling using iron oxide nanoparticles (40, 41) and Gd-HPDO3A caged in apoferritin (42). We reported recently the use of biotin-bovine serum albumin (BSA)-gadolinium-diethylenetriaminepentaacetic acid (GdDTPA) for ex vivo labeling of tumor fibroblasts (43). In the study reported here, in vivo MRI and near-IR imaging allowed detection of the recruitment of i.p. administered fibroblasts into s.c. ovarian carcinoma tumors. The recruited cells colocalized with the neovasculature at the tumor rim, suggesting the role of these stroma cells in tumor angiogenesis and their possible use for image-guided cellular targeting of tumors.
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Materials and Methods |
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-MEM. WI38 human primary lung fibroblasts were cultured in Eagle's MEM. All media were supplemented with 10% FCS (Beit Haemek), 100 units/mL penicillin, 0.1 mg/mL streptomycin, 0.06 mg/mL amphotericin B, and 2 mmol/L L-glutamine.
Tumor models. Animal experiments were approved by the Weizmann Institutional Animal Care and Use Committee. S.c. MLS tumors were generated by inoculation of 3x 106 to 5 x 106 MLS cells into the hind limb of the mouse under anesthesia [75 mg/kg ketamine i.p. (Fort Dodge Animal Health); 3 mg/kg xylazin i.p. (XYL-M2, V.M.D.)]. Several experimental designs were used (Table 1
). At the end of the imaging experiments, animals were sacrificed and tumor samples were removed and fixed in either Carnoy's solution (6:3:1 ethanol/chloroform/acetic acid) or 10% formaldehyde for H&E and Prussian blue stainings, respectively. Specimens were additionally stained for -SMA expression.
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Fluorescent and near-IR vital stains. CV-1 fibroblasts were labeled with 3.5 µg/mL of 1,1'-dioctadecyl-3,3,3'-tetramethylindotricarbocyanine iodide (DiR; Molecular Probes, Inc.) by addition of the dye into cells suspended in PBS (46). After 30-min incubation at 37°C, cells were extensively washed in PBS. For double fluorescence imaging of tumors and fibroblasts, MLS cells were stained as well with 7.5 µg/mL of 4-(4-(didecylamino)styryl)-N-methyl-pyridium iodide [4-Di-10-ASP; Molecular Probes].
Cells (tumor or fibroblasts) were labeled with carboxymethyl-1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine (CM-DiI; 7.5 µg/mL; CellTracker, Molecular Probes); 1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine, 4-chlorobenzenesulfonate salt (DiD; 7.5 µg/mL); or carboxyfluorescein diacetate, succinimidyl ester (CFSE; 5 µmol/L; Molecular Probes). Cell pellets were suspended in final concentrations in PBS and labeling was achieved by 1-h incubation, followed by extensive washes in PBS.
MRI studies. MRI was done on a horizontal 4.7-T Biospec spectrometer (Bruker) using a whole-body birdcage transmission coil. In vivo MRI measurements for detection of biotin-BSA-GdDTPA–labeled fibroblasts were done on CD-1 mice with s.c. tumors. A series of T1-weighted three-dimensional gradient-echo images, with pulse flip angles of 5, 15, 30, 50, and 70 degrees, were acquired to determine R1 values [repetition time (TR), 10 ms; echo time (TE), 3.56 ms (two averages); spectral width, 50,000 Hz; field of view, 6 x 6 x 3 cm, 128 x 128 x 64 pixels; total acquisition time per frame, 163 s]. Three-dimensional gradient-echo data sets were used for generation of R1 maps as well as for calculation of the average R1 values in selected regions of interest (Supplementary Fig. S1) by nonlinear best fit to the equation
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Feridex-labeled fibroblasts were detected in T2* weighted three-dimensional gradient-echo images (TE, 10 ms; TR, 13.56 ms; flip angle, 15 degrees, four averages; spectral width, 50,000 Hz; field of view, 6 x 6 x 3 cm, 128 x 128 x 64 pixels; zero filled to 256 x 256 x 256).
Near-IR and fluorescence imaging. In vivo near-IR images were acquired using IVIS 100 (Xenogen). The excitation and emission filter sets for DiR fluorescence were 710 to 760 and 810 to 860 nm, respectively. The excitation and emission filter sets for DiASP were 445 to 490 and 515 to 575 nm, respectively. Mice were visualized 1 to 10 days after administration of fibroblasts. At the end point of the experiment, tissues were excised and imaged as well.
Two-photon microscopy of tumors. S.c. MLS tumors were initiated in CD-1 nude mice by inoculation of 5 x 106 DiD- or CFSE-prelabeled MLS cells. After 4 days, 2 x 106 DiI- or CFSE-prelabeled CV-1 fibroblasts were injected into the peritonea of tumor-bearing mice. Imaging of the vasculature was obtained by i.v. injection of 0.2-mL dextran-FITC (2 mg/mouse; 500 KD; Sigma) before sacrifice of the mice. Excised tumors were placed in glycerol and imaged immediately by two-photon microscopy (2PM; Zeiss LSM 510 META NLO; equipped with a broadband Mai Tai-HP-femtosecond single box tunable Ti-sapphire oscillator, with automated broadband wavelength tuning 700–1,020 nm from Spectraphysics, for two-photon excitation).
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Results |
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Prolonged in vivo visibility of in vitro labeled fibroblasts. We have previously reported the short term (1–2 days) in vivo MRI visibility of fibroblasts prelabeled in vitro with biotin-BSA-GdDTPA (43). Here, we evaluated the feasibility for prolonged MRI tracking of biotin-BSA-GdDTPA–labeled fibroblasts (Table 1, Exp II). Tumors were generated in nude mice by coinoculation of MLS cells along with PFN2 primary fibroblasts that were either prelabeled (10 mg/mL biotin-BSA-GdDTPA, 48 h) or unlabeled. The visibility of prelabeled fibroblasts was determined by MRI measurements of R1 of the tumors. MRI data were acquired 1 and 8 days after inoculation of labeled and control tumors (n = 5 and n = 4, respectively). R1 values were significantly elevated in tumors with labeled fibroblasts both 1 and 8 days after inoculation (Supplementary Fig. S1). Thus, not only was a small fraction of labeled cells (10%) in the tumor volume visible after inoculation but the contrast significantly persisted for at least 8 days in vivo.
In vivo MRI detection of local fibroblast recruitment into tumors. Local recruitment of labeled cells into the tumor region was monitored by R1 measurements of tumors before and after injection of prelabeled fibroblasts (Table 1, Exp III). Fibroblasts (CV-1; labeled or unlabeled) were administered into s.c. tissue at an adjacent site to the tumor (2 mm from the tumor rim). R1 values were significantly elevated for tumors in which the administered fibroblasts were prelabeled with biotin-BSA-GdDTPA (Fig. 2
). Six days after s.c. injection of labeled fibroblasts, the average R1 value of tumors was 1.8 ± 0.1 s–1 (n = 3) whereas it was only 1.4 ± 0.1 s–1 (n = 3) in tumors with unlabeled fibroblasts (Fig. 2A; P < 0.05). Moreover, follow-up MRI studies revealed increased R1 5 and 6 days after injection of labeled cells and showed evidence for migration of the labeled fibroblasts within the tumor (Fig. 2B, b–d, arrows).
In vivo MRI detection of systemic fibroblast recruitment into tumors. Systemic recruitment of fibroblasts to the tumor was studied by MRI using CV-1 fibroblasts prelabeled with biotin-BSA-GdDTPA (Table 1, Exp IV). Fibroblasts (2 x 106 CV-1 cells, labeled or unlabeled; n = 5 for each group) were administered into the peritonea of mice with established s.c. MLS tumors in the hind limb. R1 values of tumors following i.p. injection of prelabeled fibroblasts were greater than the ones observed in the presence of unlabeled fibroblasts (Fig. 3A
; P < 0.05). Recruitment of fibroblasts was detectable as early as 2 days after administration of cells, and the elevated R1 values persisted for 6 days. However, 7 days after injection of labeled cells, the increase in R1 was no longer significant. During the 6 days of measurement, tumor size increased from 3 to 6.5 mm in diameter. Calculation of the change in R1 (
R1 = R1(labeled) – R1 (control)) suggested a similar (no significant difference) R1 for local (0.42 s–1; Fig. 2) and systemic (0.66 s–1; Fig. 3) recruitment of fibroblasts (P = 0.39).
To further validate that the signal arising at the tumor site can be attributed to the recruited fibroblasts and to exclude the possibility that the label was transferred from dying fibroblasts to phagocytic cells, we labeled CV-1 fibroblasts with iron oxide particles before their i.p. administration into tumor-bearing mice (Feridex; Table 1, Exp IV). Recruitment of iron oxide–loaded cells to the s.c. ovarian carcinoma tumors was detected in vivo by MRI (Fig. 3). Prussian blue staining of tumor specimens revealed the presence of iron oxide–loaded cells at the borders of the tumor (Fig. 3). These labeled stromal cells were elongated and possessed typical fibroblastic morphology (i.e., spindle shape with branched cytoplasm and elliptic nucleus). No iron oxide–labeled macrophages could be detected in the tumor or its vicinity. Costaining of histologic sections for -SMA and Prussian blue suggested that at the edges of the tumor, the recruited fibroblasts were undifferentiated (-SMA negative), whereas toward the tumor mass, they expressed -SMA, a marker for their differentiation to myofibroblasts (Fig. 3D, bottom).
In vivo near-IR detection of systemic fibroblast recruitment into tumors. The MRI results of systemic fibroblast recruitment into s.c. tumors were validated by near-IR fluorescence imaging (Table 1, Exp V). DiR-labeled fibroblasts (CV-1) were injected into the peritonea of nude mice bearing s.c. DiASP-labeled MLS tumors. Two days after fibroblast injection, near-IR fluorescence was not only detected at the peritoneum but was also evident at the tumor region (Fig. 4A ). Initially, the high local signal at the peritoneum site of injection saturated the camera and prevented detection of the lower signal that evolved at the tumor site. Thus, covering the mouse abdomen with a black tape was essential to reveal the tumor fluorescence. However, 7 days after fibroblast injection, the fluorescence at the tumor location increased whereas the fluorescence at the peritoneum declined, and tumor-recruited fibroblasts could be visualized even without masking of the abdomen for visualization (Fig. 4B). Fluorescence imaging of both the DiASP-labeled tumor cells and the DiR-labeled fibroblasts confirmed spatial registration of the recruited fibroblasts to the tumor (Fig. 4A and B, bottom).
The near-IR fluorescence persisted throughout the 10 days of follow-up, a time at which mice were sacrificed and tissues were excised for ex vivo near-IR fluorescence imaging (Fig. 4C). Whereas DiASP fluorescence was detected in all tumors, DiR fluorescence was only detectable in tumors generated in mice that have received fibroblasts labeled with DiR. No fluorescence was detected from the contralateral limb. The role of the tumor in inducing fibroblast recruitment was shown by injection of DiR-labeled CV-1 fibroblasts into the peritoneum of a tumor-free mouse. In the absence of a tumor, the near-IR labeled cells remained confined to the peritoneum site throughout the experimental period (10 days; Fig. 4D).
Distribution of fibroblasts in s.c. tumors after systemic recruitment. The finding that i.p. administered fibroblasts were recruited by the s.c. ovarian tumor intrigued us to further elucidate the spatial organization of these cells within the tumor. Thus, we analyzed the distribution of tumor cells, fibroblasts, and blood vessels by two-photon microscopy (Table 1, Exp VI; Fig. 5 ; Supplementary Figs. S2 and S3). Fluorescent MLS tumors were generated by s.c. inoculation of MLS ovarian cancer cells prelabeled with DiD (5 x 106 cells), followed 5 days later by i.p. injection of CV-1 fibroblasts prelabeled with CM-DiI or CFSE (2 x 106 cells; Fig. 5). Three days after i.p. administration of fibroblasts, mice were anesthetized and the vasculature was highlighted by i.v. injection of dextran-FITC into the tail vein (2 mg/mouse in 0.2 mL PBS). Mice were sacrificed 2 min afterwards and tumors were excised and visualized by two-photon microscopy. To image both the surface as well as the inner parts of the tumor, tumors that were carefully excised were sectioned in the center and both sides were imaged by two-photon microscopy. Recruited fibroblasts were predominantly present at the tumor rim (Fig. 5; Supplementary Fig. S3). Within this region, we could detect torturous capillaries, which are characteristic of tumor angiogenesis. Tumor cells, however, were not detected within this region (Fig. 5A, inner part; Supplementary data). Large dilated vessels were observed at the tumor-fibroblast interface. The same pattern was observed with fibroblasts that were labeled with CFSE as well as for tumors coinoculated with fibroblasts. Whereas recruited fibroblasts were detected at the surface of the tumor, they were absent from the inner part of the tumor (supplementary Fig. S2). The desmoplastic reaction that developed in tumors of the recruitment studies resembled that observed in specimens obtained from s.c. tumors initiated exclusively from MLS cells (Fig. 1).
Primary human fibroblasts are systemically recruited into s.c. tumors. Recruitment and distribution of human primary fibroblasts were evaluated using breast- and lung-derived fibroblasts (PFN24 and WI38, respectively) that were i.p. given into mice bearing s.c. human epithelial ovarian carcinoma MLS tumors. PFN2 fibroblasts were labeled with SPIO particles for MRI and histochemical detection, whereas WI38 were labeled with DiI for fluorescence detection (Fig. 6 ). Recruitment of the human primary fibroblasts to the tumor could be detected by all three modalities. Prussian blue staining of these tumor specimens detected labeled human primary fibroblasts in close proximity to blood vessels at the tumor rim (Fig. 6C, arrows).
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Discussion |
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In the study reported here, we applied MRI and optical imaging for studying the recruitment of fibroblasts to human ovarian carcinoma tumors. MRI tracking of cell recruitment was achieved by labeling the fibroblasts with biotin-BSA-GdDTPA. The prolonged in vivo visibility of the signal arising from biotin-BSA-GdDTPA–loaded fibroblasts is consistent with our previous in vitro studies (43) and enabled serial in vivo follow-up of fibroblast migration and recruitment to the tumor. Local and systemic recruitment of fibroblasts to s.c. ovarian carcinoma xenografts was detected by MRI and validated by in vivo near-IR imaging, revealing labeled fibroblasts at the tumor region, whereas no labeled cells could be detected in the contralateral tumor-free limb or in limbs of tumor-free mice. The identity of the recruited cells was verified by administration of fibroblasts prelabeled with iron oxide particles that could be detected both by MRI and by Prussian blue staining of histologic sections. Labeled cells recruited to the tumor rim retained the typical spindle shape characteristic of fibroblasts, thus ruling out the option of secondary transfer of label to phagocytic macrophages.
Fibroblasts were previously shown to promote the invasion of endothelial cells into three-dimensional gel matrices (48), and infiltration of tumor fibroblasts was reported to facilitate and lead the angiogenic process (12, 14). The recruitment of iron oxide–labeled EPCs into s.c. glioma tumors was recently documented by susceptibility-weighted MRI (41). SPIO-prelabeled EPCs were detectable in tumors 3 days after administration of 3 x 106 labeled EPCs. The ability to detect EPCs labeled with SPIO by T2* contrast and fibroblasts labeled with biotin-BSA-GdDTPA by T1 contrast raises the possibility to simultaneously track the role of both cells in tumor angiogenesis and tumor progression by multiparametric MRI.
The ovarian carcinoma tumors studied in this work exhibited a characteristic desmoplasia phenotype regardless of whether tumor cells were inoculated alone or fibroblasts were injected either by coinoculation or by subsequent proximal (s.c.) or distant (i.p.) administration. These results suggest that the external administration of labeled fibroblast supplemented the recruitment of endogenous fibroblasts but did not significantly alter tumor biology.
The distribution of recruited fibroblasts within the tumor mass was studied by two-photon microscopy imaging and showed recruited fibroblasts primarily at the tumor rim, coinciding with tortuous neovasculature. As opposed to these small capillaries, dilated vessels were located at the tumor-fibroblast interface. This spatial difference in vascular morphology is consistent with our previous finding that VEGF in these tumors is predominantly expressed by the MLS tumor cells whereas angiopoietin-1 and angiopoietin-2 are expressed by the stroma fibroblasts (9). The spatial organization of the recruited fibroblasts at the borders of the tumor and their colocalization with the neovasculature provide additional evidence for the role of these cells in stabilization of tumor-induced neovasculature. Additional chemoattractants, which could participate in this process, include fibroblast growth factor, PDGF, and tumor necrosis factor. Moreover, fibroblasts and myofibroblasts are known to express CXC chemokine ligand 12/stromal cell–derived factor-1 (49) that binds to its receptor CXCR4 on endothelial cells, which could then promote recruitment of endothelial cells to the rim of the tumor (12). Recruited fibroblasts may be stimulated by tumor-derived TGFß1 to differentiate into myofibroblasts and then into pericyte-like cells, which would interact with the tumor neovasculature to stabilize the vessels and regulate blood flow. Indeed, costaining of tumor specimens for -SMA expression and Prussian blue showed recruited, undifferentiated fibroblasts in close proximity to large blood vessels located at the tumor-host interface. However, in the vicinity of the tumor rim, these Prussian blue–positive fibroblasts additionally expressed -SMA, thus indicating their differentiation into myofibroblasts. We thus suggest that i.p. administered fibroblasts reach the tumor area via the blood vessels, migrate into the tumor rim, and differentiate into myofibroblasts. The precise role of these cells within the tumor remains to be studied; however, multiple studies implicated infiltrating tumor myofibroblasts in the recruitment of endothelial cells and promotion of angiogenic sprouts as well as stabilization of tumor neovascularization. The ability to track these stroma cells would help in addressing the molecular mechanisms underlying their recruitment and role in tumor progression.
In summary, we report here the extensive recruitment of prelabeled fibroblasts into the rim of ovarian carcinoma tumors, which could be followed noninvasively by both MRI and optical imaging. Uncovering the functions of fibroblasts in cancer formation and understanding the mechanism of their association with tumor and endothelial cells, as well as with other components of the tumor microenvironment, are important due to the role of these cells in tumor progression. Furthermore, the ability to noninvasively follow these cells may potentially be beneficial for using the endogenous recruitment of fibroblasts to tumors for targeted image-guided cellular therapy.
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Acknowledgments |
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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.
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Footnotes |
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Received 2/19/07. Revised 7/12/07. Accepted 7/20/07.
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References |
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(v)-integrin. Gynecol Oncol 2002;84:296–302.[CrossRef][Medline]-producing fibroblasts: comparison of constitutive and inducible vectors. Gene Ther 2006;13:953–65.[CrossRef][Medline]This article has been cited by other articles:
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  M.-F. Penet, K. Glunde, M. A. Jacobs, A. P. Pathak, and Z. M. Bhujwalla Molecular and Functional MRI of the Tumor Microenvironment J. Nucl. Med., May 1, 2008; 49(5): 687 - 690. [Full Text] [PDF]
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 Z. M Bhujwalla Molecular Imaging of the Tumor Microenvironment Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 519 - 522. [Abstract] [Full Text] [PDF]
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