Chemokines and chemokine receptors have been posited to have important roles in several common malignancies, including breast and lung cancer. Here, we demonstrate that CXCR7 (RDC1, CCX-CKR2), recently deorphanized as a chemokine receptor that binds chemokines CXCL11 and CXCL12, can regulate these two common malignancies. Using a combination of overexpression and RNA interference, we establish that CXCR7 promotes growth of tumors formed from breast and lung cancer cells and enhances experimental lung metastases in immunodeficient as well as immunocompetent mouse models of cancer. These effects did not depend on expression of the related receptor CXCR4. Furthermore, immunohistochemistry of primary human tumor tissue demonstrates extensive CXCR7 expression in human breast and lung cancers, where it is highly expressed on a majority of tumor-associated blood vessels and malignant cells but not expressed on normal vasculature. In addition, a critical role for CXCR7 in vascular formation and angiogenesis during development is demonstrated by using morpholino-mediated knockdown of CXCR7 in zebrafish. Taken together, these data suggest that CXCR7 has key functions in promoting tumor development and progression.angiogenesis ͉ cancer ͉ chemokine
Chronic obstructive pulmonary disease (COPD) is increasingly being recognized as a highly heterogeneous disorder, composed of varying pathobiology. Accurate detection of COPD subtypes by image biomarkers are urgently needed to enable individualized treatment thus improving patient outcome. We adapted the Parametric Response Map (PRM), a voxel-wise image analysis technique, for assessing COPD phenotype. We analyzed whole lung CT scans of 194 COPD individuals acquired at inspiration and expiration from the COPDGene Study. PRM identified the extent of functional small airways disease (fSAD) and emphysema as well as provided CT-based evidence that supports the concept that fSAD precedes emphysema with increasing COPD severity. PRM is a versatile imaging biomarker capable of diagnosing disease extent and phenotype, while providing detailed spatial information of disease distribution and location. PRMs ability to differentiate between specific COPD phenotypes will allow for more accurate diagnosis of individual patients complementing standard clinical techniques.
These results suggest that diffusion MRI will provide an early surrogate marker for quantification of treatment response in patients with brain tumors.
Assessment of radiation and chemotherapy efficacy for brain cancer patients is traditionally accomplished by measuring changes in tumor size several months after therapy has been administered. The ability to use noninvasive imaging during the early stages of fractionated therapy to determine whether a particular treatment will be effective would provide an opportunity to optimize individual patient management and avoid unnecessary systemic toxicity, expense, and treatment delays. We investigated whether changes in the Brownian motion of water within tumor tissue as quantified by using diffusion MRI could be used as a biomarker for early prediction of treatment response in brain cancer patients. Twenty brain tumor patients were examined by standard and diffusion MRI before initiation of treatment. Additional images were acquired 3 weeks after initiation of chemo-and͞or radiotherapy. Images were coregistered to pretreatment scans, and changes in tumor water diffusion values were calculated and displayed as a functional diffusion map (fDM) for correlation with clinical response. Of the 20 patients imaged during the course of therapy, 6 were classified as having a partial response, 6 as stable disease, and 8 as progressive disease. The fDMs were found to predict patient response at 3 weeks from the start of treatment, revealing that early changes in tumor diffusion values could be used as a prognostic indicator of subsequent volumetric tumor response. Overall, fDM analysis provided an early biomarker for predicting treatment response in brain tumor patients. diffusion MRI ͉ therapeutic response
Purpose: Development of new therapeutic drug delivery systems is an area of significant research interest. The ability to directly target a therapeutic agent to a tumor site would minimize systemic drug exposure, thus providing the potential for increasing the therapeutic index. Experimental Design: Photodynamic therapy (PDT) involves the uptake of a sensitizer by the cancer cells followed by photoirradiation to activate the sensitizer. PDTusing Photofrin has certain disadvantages that include prolonged cutaneous photosensitization. Delivery of nanoparticles encapsulated with photodynamic agent specifically to a tumor site could potentially overcome the drawbacks of systemic therapy. In this study, we have developed a multifunctional polymeric nanoparticle consisting of a surface-localized tumor vasculature targeting F3 peptide and encapsulated PDTand imaging agents. Results:The nanoparticles specifically bound to the surface of MDA-435 cells in vitro and were internalized conferring photosensitivity to the cells. Significant magnetic resonance imaging contrast enhancement was achieved in i.c. rat 9L gliomas following i.v. nanoparticle administration. Serial magnetic resonance imaging was used for determination of pharmacokinetics and distribution of nanoparticles within the tumor. Treatment of glioma-bearing rats with targeted nanoparticles followed by PDT showed a significant improvement in survival rate when compared with animals who received PDT after administration of nontargeted nanoparticles or systemic Photofrin. Conclusions:This study reveals the versatility and efficacy of the multifunctional nanoparticle for the targeted detection and treatment of cancer.Photodynamic therapy (PDT) relies on the selective uptake of a photosensitizing molecule in a tumor relative to the surrounding normal parenchyma followed by exposure to the appropriate wavelength of light to activate the photosensitizer (1). When activated by light irradiation, the photosensitizer interacts with molecular oxygen to produce a cytotoxic, shortlived species known as singlet oxygen. PDT elicits both apoptotic and necrotic responses within treated tumors and produces microvascular injury leading to inflammation and hypoxia. Photofrin, a complex mixture of porphyrin oligomers, is one of the most efficient photosensitizers approved for PDT of cancer (2). However, Photofrin can cause prolonged skin photosensitization, where patients are required to avoid direct exposure to sunlight for a period of 4 to 6 weeks. Current strategies under development include attempts to direct the photosensitizing agent to the tumor by active targeting approaches, such as peptide conjugates and antibodies (3 -7), incorporation within liposomes (8, 9), and encapsulation within polymeric nanoparticles (10 -14) in an attempt to deliver higher local concentrations at the therapeutic site.A recent report of a sub-100 nm dynamic nanoparticle platform composed of polyacrylamide, which could be loaded with a photoactivatable agent (methylene blue) for the spe...
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent endogenous activator of the cell death pathway and functions by activating the cell surface death receptors 4 and 5 (DR4 and DR5). TRAIL is nontoxic in vivo and preferentially kills neoplastically transformed cells over normal cells by an undefined mechanism. Radiotherapy is a common treatment for breast cancer as well as many other cancers. Here we demonstrate that ionizing radiation can sensitize breast carcinoma cells to TRAIL-induced apoptosis. This synergistic effect is p53-dependent and may be the result of radiation-induced up-regulation of the TRAIL-receptor DR5. Importantly, TRAIL and ionizing radiation have a synergistic effect in the regression of established breast cancer xenografts. Changes in tumor cellularity and extracellular space were monitored in vivo by diffusion-weighted magnetic resonance imaging (diffusion MRI), a noninvasive technique to produce quantitative images of the apparent mobility of water within a tissue. Increased water mobility was observed in combined TRAIL-and radiationtreated tumors but not in tumors treated with TRAIL or radiation alone. Histological analysis confirmed the loss of cellularity and increased numbers of apoptotic cells in TRAIL-and radiationtreated tumors. Taken together, our results provide support for combining radiation with TRAIL to improve tumor eradication and suggest that efficacy of apoptosis-inducing cancer therapies may be monitored noninvasively, using diffusion MRI.
Current assessment of orthotopic tumor models in animals utilizes survival as the primary therapeutic end point. In vivo bioluminescence imaging (BLI) is a sensitive imaging modality that is rapid and accessible, and may comprise an ideal tool for evaluating antineoplastic therapies. Using human tumor cell lines constitutively expressing luciferase, the kinetics of tumor growth and response to therapy have been assessed in intraperitoneal, and subcutaneous, and intravascular cancer models. However, use of this approach for evaluating orthotopic tumor models has not been demonstrated. In this report, the ability of BLI to noninvasively quantitate the growth and therapeutic-induced cell kill of orthotopic rat brain tumors derived from 9L gliosarcoma cells genetically engineered to stably express firefly luciferase (9LLuc) was investigated. Intracerebral tumor burden was monitored over time by quantitation of photon emission and tumor volume using a cryogenically cooled CCD camera and magnetic resonance imaging (MRI), respectively. There was excellent correlation (r=0.91) between detected photons and tumor volume. A quantitative comparison of tumor cell kill determined from serial MRI volume measurements and BLI photon counts following 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) treatment revealed that both imaging modalities yielded statistically similar cell kill values (P=.951). These results provide direct validation of BLI imaging as a powerful and quantitative tool for the assessment of antineoplastic therapies in living animals.
Exposure to ultraviolet light (UV) can induce apoptosis in mammalian cells. The mechanism by which UV radiation engages the suicide apparatus is unclear. Here we demonstrate that UV radiation can activate the Fas pathway via receptor aggregation and subsequent recruitment of the death adaptor molecule FADD/MORT1. UV radiation-induced apoptosis was inhibited by both a dominant negative version of FADD (FADD-DN) and the caspase inhibitor CrmA. Thus, activation of the Fas pathway represents a physiologic mechanism by which UV-damaged cells are eliminated.Depletion of the ozone layer by chloro/fluorohydrocarbon pollutants and subsequent increase in exposure to ultraviolet (UV) radiation threatens to significantly increase the incidence of skin cancer. In addition, exposure to UV radiation can lead to photokeratitis, photoconjunctivitis, and permanent retinal blindness. UV irradiation of cells elicits a complex cellular response termed the UV response, which includes the posttranslational activation of pre-existing transcription factors including NF-B and AP-1 (1, 2). Activation of these transcription factors results in the subsequent induction of proinflammatory gene products IL-1 1 and TNF-␣ (3, 4). Prolonged UV exposure results in inhibition of DNA synthesis and subsequent resumption of the cell cycle following repair or apoptosis, a mechanism to rid the organism of irreversibly damaged and potentially cancerous cells. Little is known about the mechanism by which UV radiation triggers apoptosis.It is now evident that the effector arm of the death pathway is composed of caspases, cysteine proteases that cleave death substrates including PARP and lamin B following aspartate residues (reviewed in Ref. 5). To date ten caspases have been identified. They are normally present as single polypeptide inactive zymogens and require cleavage at internal aspartic acid residues to generate the 2-subunit catalytically competent protease. The best understood pathway leading to caspase activation is engagement of the death receptor, CD-95 (Fas/APO-1). Upon activation, an adapter molecule termed FADD is recruited to the cytoplasmic segment of the Fas receptor through a homophilic interaction between a stretch of 60 -80 amino acids, dubbed the death domain that is present in both molecules. The N-terminal segment of FADD encodes a distinct binding module termed the death effector domain (6). Remarkably, an equivalent domain, is present within the prodomain of FLICE (caspase-8). Interaction between the death effector domains allows for the recruitment of the death protease FLICE to the receptor signaling complex. Following conversion to the active dimeric species, FLICE is free to proteolytically activate other downstream zymogen caspases (7), leading to cleavage of death substrates and subsequent apoptotic demise.The ability of enucleated cells to mount a UV response has led to the suggestion that membrane or cytosolic events likely mediate the response (8). UV exposure for example induces rapid tyrosine phosphorylation of the EGF r...
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