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ABSTRACT: Background. A high fraction of stroma in malignant tissues is associated with tumor progression, metastasis, and poor prognosis. Possible correlations between the stromal and physiologic microenvironments of tumors and the potential of dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) in quantification of the stromal microenvironment were investigated in this study. Material and methods. CK-160 cervical carcinoma xenografts were used as preclinical tumor model. A total of 43 tumors were included in the study, and of these tumors, 17 were used to search for correlations between the stromal and physiologic microenvironments, 11 were subjected to DCE-MRI, and 15 were subjected to DW-MRI. DCE-MRI and DW-MRI were carried out at 1.5 T with a clinical MR scanner and a slotted tube resonator transceiver coil constructed for mice. Fraction of connective tissue (CTFCol) and fraction of hypoxic tissue (HFPim) were determined by immunohistochemistry. A Millar SPC 320 catheter was used to measure tumor interstitial fluid pressure (IFP). Results. CTFCol showed a positive correlation to IFP and an inverse correlation to HFPim. The apparent diffusion coefficient assessed by DW-MRI was inversely correlated to CTFCol, whereas no correlation was found between DCE-MRI-derived parameters and CTFCol. Conclusion. DW-MRI is a potentially useful method for characterizing the stromal microenvironment of tumors.
Acta oncologica (Stockholm, Sweden) 02/2013; · 2.27 Impact Factor
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ABSTRACT: BACKGROUND: High interstitial fluid pressure (IFP) in the primary tumor is associated with poor disease-free survival in locally advanced cervical carcinoma. A noninvasive assay is needed to identify cervical cancer patients with highly elevated tumor IFP because these patients may benefit from particularly aggressive treatment. It has been suggested that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA) as contrast agent may provide useful information on the IFP of cervical carcinomas. In this preclinical study, we investigated whether DCE-MRI with contrast agents with higher molecular weights (MW) than Gd-DTPA would be superior to Gd-DTPA-based DCE-MRI. METHODS: CK-160 human cervical carcinoma xenografts were subjected to DCE-MRI with Gd-DTPA (MW of 0.55 kDa) or gadomelitol (MW of 6.5 kDa) as contrast agent before tumor IFP was measured invasively with a Millar SPC 320 catheter. The DCE-MRI was carried out at a spatial resolution of 0.23 x 0.23 x 2.0 mm3 and a time resolution of 14 s by using a 1.5-T whole-body scanner and a slotted tube resonator transceiver coil constructed for mice. Parametric images were derived from the DCE-MRI recordings by using the Tofts iso-directional transport model and the Patlak uni-directional transport model. RESULTS: When gadomelitol was used as contrast agent, significant positive correlations were found between the parameters of both pharmacokinetic models and tumor IFP. On the other hand, significant correlations between DCE-MRI-derived parameters and IFP could not be detected with Gd-DTPA as contrast agent. CONCLUSION: Gadomelitol is a superior contrast agent to Gd-DTPA in DCE-MRI of the IFP of CK-160 cervical carcinoma xenografts. Clinical studies attempting to develop DCE-MRI-based assays of the IFP of cervical carcinomas should involve contrast agents with higher MW than Gd-DTPA.
BMC Cancer 11/2012; 12(1):544. · 3.01 Impact Factor
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ABSTRACT: Background. Cancer patients showing highly elevated interstitial fluid pressure (IFP) in the primary tumor may benefit from particularly aggressive treatment. There is some evidence that gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may be a useful non-invasive method for providing information on the IFP of tumors. The purpose of this preclinical study was to investigate whether any association between DCE-MRI-derived parametric images and tumor IFP can be strengthened by using MR contrast agents with higher molecular weights than that of Gd-DTPA. Material and methods. A-07 human melanoma xenografts were used as preclinical models of human cancer. Three contrast agents were compared: Gd-DTPA (0.55 kDa), P846 (3.5 kDa), and gadomelitol (6.5 kDa). A total of 46 tumors were subjected to DCE-MRI and subsequent measurement of IFP. Parametric images of K(trans) (the volume transfer constant of the contrast agent) and v(e) (the fractional distribution volume of the contrast agent) were produced by pharmacokinetic analysis of the DCE-MRI series. Results. Significant inverse correlations were found between median K(trans) and IFP for Gd-DTPA (p = 0.0076; R(2) = 0.46; n = 14) and P846 (p = 0.0042; R(2) = 0.45; n = 16), whereas there was no correlation between median K(trans) and IFP for gadomelitol (p > 0.05; n = 16). Significant correlation between median v(e) and IFP was not found for any of the contrast agents (p > 0.05 for Gd-DTPA, P846, and gadomelitol). Conclusion. K(trans) images, but not v(e) images, derived by pharmacokinetic analysis of DCE-MRI data for low-molecular-weight contrast agents may provide information on the IFP of tumors. Any association between K(trans) and IFP cannot be expected to be improved by using contrast agents with higher molecular weights than those of Gd-DTPA and P846.
Acta oncologica (Stockholm, Sweden) 11/2012; · 2.27 Impact Factor
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ABSTRACT: Elevated interstitial fluid pressure (IFP) in tumors can cause metastatic dissemination and treatment resistance, but its study poses a challenge because of a paucity of noninvasive imaging strategies. In this study, we address this issue by reporting the development of a noninvasive tool to assess tumor IFP and interstitial hypertension-induced lymph node metastasis. Using mouse xenograft models of several types of human cancer, we used gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA) as a contrast agent for dynamic contrast-enhanced MRI (DCE-MRI). Immediately after Gd-DTPA administration, a high-signal-intensity rim was observed in the tumor periphery, which moved outward with time. Assuming the velocity of Gd-DTPA to be equal to the fluid flow velocity, we used a simple model of peritumoral interstitial fluid flow to calculate the fluid flow velocity at the tumor surface (v(0)) based on the rim movement. Significant positive correlations were found between v(0) and IFP in all tumor xenografts. Moreover, the primary tumors of metastasis-positive mice displayed higher IFP and v(0) than the primary tumors of metastasis-negative mice. Findings were confirmed in cervical cancer patients with pelvic lymph node metastases, where we found v(0) to be higher compared with patients without lymph node involvement (P < 0.00001). Together, these findings establish that Gd-DTPA-based DCE-MRI can noninvasively visualize tumor IFP, and they reveal the potential for v(0) determined by this method to serve as a novel general biomarker of tumor aggressiveness. Cancer Res; 72(19); 4899-908. ©2012 AACR.
Cancer Research 10/2012; 72(19):4899-908. · 7.86 Impact Factor
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ABSTRACT: Background. Gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been suggested to be a useful non-invasive method for providing biomarkers for personalized cancer treatment. In this preclinical study, we investigated whether Gd-DTPA-based DCE-MRI may have the potential to differentiate between poorly and highly metastatic tumors. Material and methods. CK-160 cervical carcinoma and V-27 melanoma xenografts were used as tumor models. Fifty-six tumors were imaged, and parametric images of Ktrans (the volume transfer constant of Gd-DTPA) and v(e) (the fractional distribution volume of Gd-DTPA) were produced by pharmacokinetic analysis of the DCE-MRI series. The host mice were examined for lymph node metastases immediately after the DCE-MRI. Results. Highly metastatic tumors showed lower values for median Ktrans than poorly metastatic tumors (p = 0.00033, CK-160; p < 0.00001, V-27). Median v(e) was lower for highly than for poorly metastatic V-27 tumors (p = 0.047), but did not differ significantly between metastatic and non-metastatic CK-160 tumors (p > 0.05). Conclusion. This study supports the clinical attempts to establish DCE-MRI as a method for providing biomarkers for tumor aggressiveness and suggests that tumors showing low K(trans) and low v(e) values may have high probability of lymphogenous metastatic dissemination.
Acta oncologica (Stockholm, Sweden) 06/2012; · 2.27 Impact Factor
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ABSTRACT: The prognosis is particularly poor for patients with advanced squamous cell carcinoma of the uterine cervix when the primary tumor has developed severe physiological abnormalities. The impact of the physiological microenvironment of the primary tumor on lymph node metastasis was investigated in this preclinical study.
Xenografted tumors of two human cervical carcinoma lines (CK-160 and TS-415) transplanted into BALB/c nu/nu mice were included in the study. The fraction of radiobiologically hypoxic cells (HF(Rad)), interstitial fluid pressure (IFP), and extracellular pH (pH(e)) were measured in 22 CK-160 tumors and 16 TS-415 tumors and related to the metastatic status of the host mice.
In CK-160, HF(Rad) was significantly higher in the metastatic than in the nonmetastatic tumors, whereas the metastatic and nonmetastatic tumors did not differ significantly in IFP or pH(e). In TS-415, IFP was significantly higher in the tumors that metastasized than in those that did not metastasize, whereas the tumors of the metastasis-positive and metastasis-negative mice did not differ significantly in HF(Rad) or pH(e).
Lymph node metastasis is associated with abnormalities in the physiological microenvironment of the primary tumor in cervical carcinoma xenografts, and tumor line-specific mechanisms are probably involved.
Acta oncologica (Stockholm, Sweden) 01/2012; 51(4):465-72. · 2.27 Impact Factor
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ABSTRACT: Studies of intradermal melanoma xenografts have suggested that dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may be a useful method for assessing the extent of hypoxia in tumors. Because the microvascular network of tumors is influenced significantly by the site of growth, we challenged this possibility in the present work by studying relationships between DCE-MRI-derived parameters and hypoxia in intramuscular melanoma xenografts.
Intramuscular R-18, U-25, and V-27 tumors were subjected to DCE-MRI and measurement of the fraction of radiobiologically hypoxic cells (HF(Rad)). Parametric images of K(trans) and v(e) were produced by pharmacokinetic analysis, and K(trans) and v(e) were related to HF(Rad) in individual tumors.
K(trans) decreased with increasing HF(Rad). The correlations between K(trans) and HF(Rad) were similar for the three tumor lines and were highly significant (P<0.00001). There was no correlation between v(e) and HF(Rad). However, v(e) decreased significantly with increasing cell survival after single dose irradiation.
Intramuscular melanoma xenografts show similar inverse correlations between K(trans) and HF(Rad) as intradermal tumors, which support the current clinical attempts to establish DCE-MRI as a method for detecting hypoxia and defining therapeutic targets in tumors.
Radiotherapy and Oncology 12/2011; 102(3):429-35. · 5.58 Impact Factor
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ABSTRACT: Extensive hypoxia and high interstitial fluid pressure (IFP) in the primary tumor may cause resistance to radiation treatment and promote metastatic spread. The potential of gadomelitol-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in assessing the extent of hypoxia and the level of interstitial hypertension in tumors was investigated in this preclinical study.
Twenty-three A-07 tumors were subjected to DCE-MRI and subsequent measurement of IFP and fraction of pimonidazole-positive hypoxic tissue (HF(Pim)). Parametric tumor images of K(trans), v(e), and V(b)(Tofts) (Tofts model) and of K(i) and V(b)(Patlak) (Patlak model) were produced by pharmacokinetic analyses of the DCE-MRI series.
There was no correlation between IFP and HF(Pim) in the tumors. K(trans) and K(i) decreased significantly with increasing HF(Pim), whereas V(b)(Tofts) and V(b)(Patlak) increased significantly with increasing IFP.
Information on both the extent of hypoxia and the level of interstitial hypertension in A-07 tumors can be derived from a single DCE-MRI series by using gadomelitol as contrast agent.
Radiotherapy and Oncology 08/2011; 101(1):217-22. · 5.58 Impact Factor
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ABSTRACT: The fibrillar collagen network in tumor and normal tissues is different due to remodeling of the extracellular matrix during the malignant process. Collagen type I fibers have the crystalline and noncentrosymmetric properties required for generating the second-harmonic signal. The content and structure of collagen were studied by imaging the second-harmonic generation (SHG) signal in frozen sections from three tumor tissues, osteosarcoma, breast carcinoma, and melanoma, and were compared with corresponding normal tissues, bone/femur, breast, and dermis/skin. The collagen density was measured as the percentage of pixels containing SHG signal in tissue images, and material parameters such as the second-order nonlinear optical susceptibility given by the d22 coefficient and an empirical anisotropy parameter were used to characterize the collagen structure. Generally, normal tissues had much more collagen than tumor tissues. In tumor tissues, a cap of collagen was seen at the periphery, and further into the tumors, the distribution of collagen was sparse and heterogeneous. The difference in structure was reflected in the two times higher d22 coefficient and lower anisotropy values in normal tissues compared with tumor tissues. Together, the differences in the collagen content, distribution, and structure show that collagen signature is a promising diagnostic marker.
Journal of Biomedical Optics 13(5):054050. · 3.16 Impact Factor
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ABSTRACT: Characteristic changes in the organization of fibrillar collagen can potentially serve as an early diagnostic marker in various pathological processes. Tissue types containing collagen I can be probed by pulsed high-intensity laser radiation, thereby generating second harmonic light that provides information about the composition and structure at a microscopic level. A technique was developed to determine the essential second harmonic generation (SHG) parameters in a laser scanning microscope setup. A rat-tail tendon frozen section was rotated in the xy-plane with the pulsed laser light propagating along the z-axis. By analyzing the generated second harmonic light in the forward direction with parallel and crossed polarizer relative to the polarization of the excitation laser beam, the second-order nonlinear optical susceptibilities of the collagen fiber were determined. Systematic variations in SHG response between ordered and less ordered structures were recorded and evaluated. A 500 microm-thick z-cut lithiumniobate (LiNbO(3)) was used as reference. The method was applied on frozen sections of malignant melanoma and normal skin tissue. Significant differences were found in the values of d(22), indicating that this parameter has a potential role in differentiating between normal and pathological processes.
Journal of Biomedical Optics 12(4):044002. · 3.16 Impact Factor
