Christophe F. Chantrain

Bio: Christophe F. Chantrain is an academic researcher from University of Southern California. The author has contributed to research in topics: Prinomastat & Matrix metalloproteinase. The author has an hindex of 4, co-authored 4 publications receiving 375 citations. Previous affiliations of Christophe F. Chantrain include Children's Hospital Los Angeles.

Stromal Matrix Metalloproteinase-9 Regulates the Vascular Architecture in Neuroblastoma by Promoting Pericyte Recruitment

Abstract: Advanced stages of neuroblastoma show increased expression of matrix metalloproteinases MMP-2 and MMP-9 (Y. Sugiura et al ., Cancer Res., 58: 2209–2216, 1998) that have been implicated in many steps of tumor progression, suggesting that they play a contributory role. Using pharmacological and genetic approaches, we have examined the role of these MMPs in progression of SK-N-BE (2).10 human neuroblastoma tumors orthotopically xenotransplanted into immunodeficient mice. Mice treated with Prinomastat, a synthetic inhibitor of MMPs, showed an inhibition of tumor cell proliferation in implanted tumors and a prolonged survival (50 versus 39 days in control group, P < 0.035). Treatment with Prinomastat did not affect formation of liver metastases ( P = 0.52) but inhibited intravascular colonization by the tumor cells in the lung by 73.8% ( P = 0.03) and angiogenesis in both primary tumors and experimental liver metastases. The primary tumors from Prinomastat-treated mice showed a 39.3% reduction in endothelial area detected by PECAM/CD31 staining in tumor sections ( P < 0.001), primarily due to the presence of smaller vessels ( P = 0.004). MMP-2 is expressed by neuroblastoma tumor cells and stromal cells, whereas MMP-9 is exclusively expressed by stromal cells, particularly vascular cells. To examine the contribution of MMP-9 to tumor angiogenesis, we generated RAG1/MMP-9 double-deficient mice. We observed a significant inhibition of angiogenesis in the immunodeficient RAG1/MMP-9 double-deficient mice orthotopically implanted with tumor cells ( P = 0.043) or implanted s.c. with a mixture of tumor cells and Matrigel ( P < 0.001). Using an FITC-labeled lectin, we demonstrated an inhibition in the architecture of the tumor vasculature in MMP-9-deficient mice, resulting in fewer and smaller blood vessels. These changes were associated with a 48% decrease in pericytes present along microvessels. Taken together, the data demonstrate that in neuroblastoma, stromally derived MMP-9 contributes to angiogenesis by promoting blood vessel morphogenesis and pericyte recruitment.

The Matrix Metalloproteinase Inhibitor Prinomastat Enhances Photodynamic Therapy Responsiveness in a Mouse Tumor Model

Abstract: Photodynamic therapy (PDT) clinical results are promising; however, tumor recurrences can occur and, therefore, methods for improving treatment efficacy are needed. PDT elicits direct tumor cell death and microvascular injury as well as expression of angiogenic, inflammatory, and prosurvival molecules. Preclinical studies combining antiangiogenic drugs or cyclooxygenase-2 inhibitors with PDT show improved treatment responsiveness (A. Ferrario et al., Cancer Res 2000;60:4066-9; A. Ferrario et al., Cancer Res 2002;62:3956-61). In the present study, we evaluated the role of Photofrin-mediated PDT in eliciting expression of matrix metalloproteinases (MMPs) and modulators of MMP activity. We also examined the efficacy of a synthetic MMP inhibitor, Prinomastat, to enhance tumoricidal activity after PDT, using a mouse mammary tumor model. Immunoblot analysis of extracts from PDT-treated tumors demonstrated strong expression of MMPs and extracellular MMP inducer along with a concomitant decrease in expression of tissue inhibitor of metalloproteinase-1. Gelatin zymography and enzyme activity assays performed on protein extracts from treated tumors confirmed the induction of both latent and enzymatically active forms of MMP-9. Immunohistochemical analysis indicated that infiltrating inflammatory cells and endothelial cells were primary sources of MMP-9 expression after PDT, whereas negligible expression was observed in tumor cells. Administration of Prinomastat significantly improved PDT-mediated tumor response (P = 0.02) without affecting normal skin photosensitization. Our results indicate that PDT induces MMPs and that the adjunctive use of an MMP inhibitor can improve PDT tumor responsiveness.

Computerized Quantification of Tissue Vascularization Using High-resolution Slide Scanning of Whole Tumor Sections

Abstract: Assessment of tissue vascularization using immunohistochemical techniques for microvessel detection has been limited by difficulties in generating reproducible quantitative data. The distinction of individual blood vessels and the selection of microscopic fields to be analyzed remain two factors of subjectivity. In this study, we used imaging analysis software and a high-resolution slide scanner for measurement of CD31-immunostained endothelial area (EA) in whole sections of human neuroblastoma xenograft and murine mammary adenocarcinoma tumors. Imaging analysis software provided objective criteria for analysis of sections of different tumors. The use of the criteria on images of entire tumor section acquired with the slide scanner constituted a rapid method to quantify tumor vascularization. Compared with previously described methods, the "hot spot" and the "random fields" methods, EA measurements obtained with our "whole section scanning" method were more reproducible with 8.6% interobserver disagreement for the "whole section scanning" method vs 42.2% and 39.0% interobserver disagreement for the "hot spot" method and the "random fields," respectively. Microvessel density was also measured with the whole section scanning method and provided additional data on the distribution and the size of the blood vessels. Therefore, this method constitutes a time efficient and reproducible method for quantification of tumor vascularization.

Les métalloprotéases matricielles et leurs inhibiteurs synthétiques dans la progression tumorale

Abstract: Les metalloproteases matricielles (MMP) constituent une famille de proteases impliquees dans la degradation proteolytique de nombreuses proteines de la matrice extracellulaire mais aussi de proteines non matricielles. Ces proteases jouent un role important et complexe dans plusieurs etapes de la progression cancereuse telles que la croissance tumorale, la proliferation des cellules cancereuses et leur caractere invasif, la dissemination metastatique et l’angiogenese. Les MMP sont donc devenues des cibles potentielles dans le traitement anti-cancereux. Plusieurs inhibiteurs synthetiques ont ainsi ete developpes et ont montre une efficacite therapeutique dans plusieurs modeles animaux de cancer. Les premiers essais cliniques realises avec ces inhibiteurs chez des patients cancereux a un stade avance ont cependant montre des effets mitiges.

Photodynamic therapy of cancer: An update†‡

Abstract: Photodynamic therapy (PDT) is a clinically approved, minimally invasive therapeutic procedure that can exert a selective cytotoxic activity toward malignant cells. The procedure involves administration of a photosensitizing agent followed by irradiation at a wavelength corresponding to an absorbance band of the sensitizer. In the presence of oxygen, a series of events lead to direct tumor cell death, damage to the microvasculature, and induction of a local inflammatory reaction. Clinical studies revealed that PDT can be curative, particularly in early stage tumors. It can prolong survival in patients with inoperable cancers and significantly improve quality of life. Minimal normal tissue toxicity, negligible systemic effects, greatly reduced long-term morbidity, lack of intrinsic or acquired resistance mechanisms, and excellent cosmetic as well as organ function-sparing effects of this treatment make it a valuable therapeutic option for combination treatments. With a number of recent technological improvements, PDT has the potential to become integrated into the mainstream of cancer treatment. CA Cancer J Clin 2011;61:250-281. V C

Matrix metalloproteinases and the regulation of tissue remodelling

Abstract: Matrix metalloproteinases (MMPs) were discovered because of their role in amphibian metamorphosis, yet they have attracted more attention because of their roles in disease. Despite intensive scrutiny in vitro, in cell culture and in animal models, the normal physiological roles of these extracellular proteases have been elusive. Recent studies in mice and flies point to essential roles of MMPs as mediators of change and physical adaptation in tissues, whether developmentally regulated, environmentally induced or disease associated.

Imaging and photodynamic therapy: mechanisms, monitoring, and optimization.

Abstract: 1.1 Photodynamic Therapy and Imaging The purpose of this review is to present the current state of the role of imaging in photodynamic therapy (PDT). In order for the reader to fully appreciate the context of the discussions embodied in this article we begin with an overview of the PDT process, starting with a brief historical perspective followed by detailed discussions of specific applications of imaging in PDT. Each section starts with an overview of the specific topic and, where appropriate, ends with summary and future directions. The review closes with the authors’ perspective of the areas of future emphasis and promise. The basic premise of this review is that a combination of imaging and PDT will provide improved research and therapeutic strategies. PDT is a photochemistry-based approach that uses a light-activatable chemical, termed a photosensitizer (PS), and light of an appropriate wavelength, to impart cytotoxicity via the generation of reactive molecular species (Figure 1a). In clinical settings, the PS is typically administered intravenously or topically, followed by illumination using a light delivery system suitable for the anatomical site being treated (Figure 1b). The time delay, often referred to as drug-light interval, between PS administration and the start of illumination with currently used PSs varies from 5 minutes to 24 hours or more depending on the specific PS and the target disease. Strictly speaking, this should be referred to as the PS-light interval, as at the concentrations typically used the PS is not a drug, but the drug-light interval terminology seems to be used fairly frequently. Typically, the useful range of wavelengths for therapeutic activation of the PS is 600 to 800 nm, to avoid interference by endogenous chromophores within the body, and yet maintain the energetics necessary for the generation of cytotoxic species (as discussed below) such as singlet oxygen (1O2). However, it is important to note that photosensitizers can also serve as fluorescence imaging agents for which activation with light in the 400nm range is often used and has been extremely useful in diagnostic imaging applications as described extensively in Section 2 of this review. The obvious limitation of short wavelength excitation is the lack of tissue penetration so that the volumes that are probed under these conditions are relatively shallow. Open in a separate window Figure 1 (A) A schematic representation of PDT where PS is a photoactivatable multifunctional agent, which, upon light activation can serve as both an imaging agent and a therapeutic agent. (B) A schematic representation of the sequence of administration, localization and light activation of the PS for PDT or fluorescence imaging. Typically the PS is delivered systemically and allowed to circulate for an appropriate time interval (the “drug-light interval”), during which the PS accumulates preferentially in the target lesion(s) prior to light activation. In the idealized depiction here the PS is accumulation is shown to be entirely in the target tissue, however, even if this is not the case, light delivery confers a second layer of selectivity so that the cytotoxic effect will be generated only in regions where both drug and light are present. Upon localization of the PS, light activation will result in fluorescence emission which can be implemented for imaging applications, as well as generation cytotoxic species for therapy. In the former case light activation is achieved with a low fluence rate to generate fluorescence emission with little or no cytotoxic effect, while in the latter case a high fluence rate is used to generate a sufficient concentration of cytotoxic species to achieve biological effects.

Matrix metalloproteinases and tumor metastasis

Abstract: Functions of individual matrix metalloproteinases (MMPs) differentially expressed by tumor cells and stromal cells, are finely regulated by their spatial as well as temporal interactions with distinct cellular and extracellular components of the tumor microenvironment and also distant pre-metastatic sites. Certain aspects of MMP involvement in tumor metastasis such as tumor-induced angiogenesis, tumor invasion, and establishment of metastatic foci at the secondary site, have received extensive attention that resulted in an overwhelming amount of experimental and observational data in favor of critical roles of MMPs in these processes. In particular, dependency of tumor angiogenesis on the activity of MMPs, especially that of MMP-9, renders this step possibly the most effective target of synthetic MMP inhibitors. MMP functioning in other stages of metastasis, including the escape of individual tumor cells from the primary tumor, their intravasation, survival in circulation, and extravasation at the secondary site, have not yet received enough consideration, resulting in insufficient or controversial data. The major pieces of evidence that are most compelling and clearly determine the role and involvement of MMPs in the metastatic cascade are provided by molecular genetic studies employing knock-out or transgenic animals and tumor cell lines, modified to overexpress or downregulate a specific MMP. Findings from all of these studies implicate different functional mechanisms for both tumor and stromal MMPs during distinct steps of the metastatic cascade and indicate that MMPs can exhibit pro-metastatic as well as anti-metastatic roles depending on their nature and the experimental setting. This dual function of individual MMPs in metastasis has become a major focus of this review.