Exosomes are nanometer-sized lipid vesicles released ubiquitously by cells, which have been shown to have a normal physiological role, as well as influence the tumor microenvironment and aid metastasis. Recent studies highlight the ability of exosomes to convey tumor-suppressive and oncogenic mRNAs, microRNAs, and proteins to a receiving cell, subsequently activating downstream signaling pathways and influencing cellular phenotype. Here, we show that radiation increases the abundance of exosomes released by glioblastoma cells and normal astrocytes. Exosomes derived from irradiated cells enhanced the migration of recipient cells, and their molecular profiling revealed an abundance of molecules related to signaling pathways important for cell migration. In particular, connective tissue growth factor (CTGF) mRNA and insulin-like growth factor binding protein 2 (IGFBP2) protein levels were elevated, and coculture of nonirradiated cells with exosomes isolated from irradiated cells increased CTGF protein expression in the recipient cells. Additionally, these exosomes enhanced the activation of neurotrophic tyrosine kinase receptor type 1 (TrkA), focal adhesion kinase, Paxillin, and proto-oncogene tyrosine-protein kinase Src (Src) in recipient cells, molecules involved in cell migration. Collectively, our data suggest that radiation influences exosome abundance, specifically alters their molecular composition, and on uptake, promotes a migratory phenotype.

Chand Khanna and colleagues describe the work of the Comparative Oncology Trials Consortium (COTC), which provides infrastructure and resources to integrate naturally occurring dog cancer models into the development of new human cancer drugs, devices, and imaging techniques.

Treatment of cats with SCC of the nasal planum with a single fraction of (90)Sr appeared to be effective and well tolerated. Initial response to treatment was predictive of overall survival time.

The positioning accuracy and precision of a head and neck immobilization device for radiation therapy of tumors in the canine skull was evaluated. Nineteen dogs with a spontaneous tumor of the head were enrolled including 12 with an intracranial mass and seven with an intranasal or maxillary tumor. Three hundred thirty-three pairs of orthogonal digital portal radiographs were analyzed to assess patient displacement in the cranial-caudal, lateral, and dorso-ventral directions. The mean systematic displacement was 0.8, 1, and 0.9 mm. The mean random displacement was 1.9, 1.6, and 1.5 mm. These values resulted in an overall displacement of 2.1 mm in the cranial-caudal direction, 1.8mm in the lateral direction, and 1.7 mm in the dorsal-ventral direction. The mean displacement value of the three dimensional (3D) vector was 2.4 mm with a standard deviation of 2.1. Ninety-five percent of all vectors were < 6.4 mm. This study quantifies the precision and accuracy of this particular positioning device. Knowing the limitations and setup variability of the system being used to set patients up for daily radiotherapy is paramount to planning and delivering appropriate radiation doses, especially as more complex treatment methods are used.

Objective To evaluate changes in characteristics of feline injection-site sarcomas (ISSs) from 1990 through 2006. Design Retrospective case series. Animals 392 cats with a histologic diagnosis of soft tissue sarcoma, osteosarcoma, or chondrosarcoma at potential injection sites. Procedures Classification and anatomic location of tumors and signalment of affected cats were compared between ISSs diagnosed before and after publication of the Vaccine Associated Feline Sarcoma Task Force vaccination recommendations in 1996. Results From before to after publication of the vaccination recommendations, proportions of ISSs significantly decreased in the interscapular (53.4% to 39.5%) and right and left thoracic (10.2% to 3.6% and 9.1% to 1.3%, respectively) regions. On the other hand, proportions of ISSs significantly increased in the right thoracic limb (1.1% to 9.5%) and the combined regions of the right pelvic limb with right lateral aspect of the abdomen (12.5% to 25.0%) and the left pelvic limb with left lateral aspect of the abdomen (11.4% to 13.8%). Patterns of tumor classification and signalment did not change. Conclusions and Clinical Relevance Despite publication of the vaccination recommendations, a high proportion of tumors still developed in the interscapular region. There was also an increase in lateral abdominal ISSs, which are more difficult to treat and are likely attributable to aberrant placement of injections intended for the pelvic limbs. Veterinarians are complying with vaccination recommendations to some extent, but they need to focus on administering vaccines as distally as possible on a limb to allow for complete surgical margins if amputation of a limb is required.

Protein Phosphatase 2A (PP2A) is a tumor suppressor whose function is lost in many cancers. An emerging, though counterintuitive, therapeutic approach is inhibition of PP2A to drive damaged cells through the cell cycle, sensitizing them to radiation therapy. We investigated the effects of PP2A inhibition on U251 glioblastoma cells following radiation treatment in vitro and in a xenograft mouse model in vivo. Radiation therapy alone augmented PP2A activity, though this was significantly attenuated with combination LB100 treatment. LB100 treatment yielded a radiation dose enhancement factor of 1.45 and increased the rate of post-radiation mitotic catastrophe at 72 and 96 hours. Glioblastoma cells treated with combination LB100 and radiation therapy maintained increased γ-H2AX expression at 24 hours, diminishing cellular repair of radiation-induced DNA double-strand breaks. Combination therapy significantly enhanced tumor growth delay and mouse survival and decreased p53 expression 3.68-fold, compared to radiation therapy alone. LB100 treatment effectively inhibited PP2A activity and enhanced U251 glioblastoma radiosensitivity in vitro and in vivo. Combination treatment with LB100 and radiation significantly delayed tumor growth, prolonging survival. The mechanism of radiosensitization appears to be related to increased mitotic catastrophe, decreased capacity for repair of DNA double-strand breaks, and diminished p53 DNA damage response pathway activity.

These data indicated that mTOR and its downstream product are present and active in canine osteosarcoma cells. The pathway can be inhibited by rapamycin, and treatment of cells with rapamycin decreased the surviving tumor cell fraction. These data support the molecular basis for further investigation into the use of mTOR inhibitors as an antineoplastic approach for dogs with osteosarcoma.

Successful development of novel cancer drugs depends on well-reasoned scientific drug discovery, rigorous preclinical development, and carefully conceived clinical trials. Failure in any of these steps contributes to poor rates of approval for new drugs to treat cancer. As technological and scientific advances have opened the door to a variety of novel approaches to cancer drug discovery and development, preclinical models that can answer questions about the activity and safety of novel therapies are increasingly necessary. The advance of a drug to clinical trials based on information from preclinical models presupposes that the models convey informative data for future use in human patients with cancer. The study of novel cancer drugs using in vitro models is highly controllable, reproducible, relatively inexpensive, and linked to high throughput. However, these models fail to reproduce many of the complex features of human cancer. Mouse models address some of these limitations but have important biological differences from human cancer. The integration of studies using pet dogs with spontaneously occurring tumors as models in the development path can answer questions not adequately addressed in conventional models and is therefore gaining attention and interest in drug development communities. The study of novel cancer drugs in dogs with naturally occurring tumors allows drug assessment in a cancer that shares many fundamental features with the human cancer condition, and thus provides an opportunity to answer questions that inform the cancer drug development path in ways not possible in more conventional models.