Extracellular Matrix Proteins and Tumor Angiogenesis

Tumor development is a complex process that relies on interaction and communication between a number of cellular compartments. Much of the mass of a solid tumor is comprised of the stroma which is richly invested with extracellular matrix. Within this matrix are a host of matricellular proteins that regulate the expression and function of a myriad of proteins that regulate tumorigenic processes. One of the processes that is vital to tumor growth and progression is angiogenesis, or the formation of new blood vessels from preexisting vasculature. Within the extracellular matrix are structural proteins, a host of proteases, and resident pro- and antiangiogenic factors that control tumor angiogenesis in a tightly regulated fashion. This paper discusses the role that the extracellular matrix and ECM proteins play in the regulation of tumor angiogenesis

Ovine Pulmonary Adenocarcinoma: A Unique Model to Improve Lung Cancer Research

Lung cancer represents a major worldwide health concern; although advances in patient management have improved outcomes for some patients, overall 5-year survival rates are only around 15%. In vitro studies and mouse models are commonly used to study lung cancer and their use has increased the molecular understanding of the disease. Unfortunately, mouse models are poor predictors of clinical outcome and seldom mimic advanced stages of the human disease. Animal models that more accurately reflect human disease are required for progress to be made in improving treatment outcomes and prognosis. Similarities in pulmonary anatomy and physiology potentially make sheep better models for studying human lung function and disease. Ovine pulmonary adenocarcinoma (OPA) is a naturally occurring lung cancer that is caused by the jaagsiekte sheep retrovirus. The disease is endemic in many countries throughout the world and has several features in common with human lung adenocarcinomas, including histological classification and activation of common cellular signaling pathways. Here we discuss the in vivo and in vitro OPA models that are currently available and describe the advantages of using pre-clinical naturally occurring OPA cases as a translational animal model for human lung adenocarcinoma. The challenges and options for obtaining these OPA cases for research purposes, along with their use in developing novel techniques for the evaluation of chemotherapeutic agents or for monitoring the tumor microenvironment in response to treatment, are also discussed

Opposing Functions of Akt Isoforms in Lung Tumor Initiation and Progression

<div><p>Background</p><p>The phosphatidylinositol 3-kinase–regulated protein kinase, Akt, plays an important role in the initiation and progression of human cancer. Mammalian cells express three Akt isoforms (Akt1–3), which are encoded by distinct genes. Despite sharing a high degree of amino acid identity, phenotypes observed in knockout mice suggest that Akt isoforms are not functionally redundant. The relative contributions of the different Akt isoforms to oncogenesis, and the effect of their deficiencies on tumor development, are not well understood.</p><p>Methods</p><p>Here we demonstrate that Akt isoforms have non-overlapping and sometimes opposing functions in tumor initiation and progression using a viral oncogene-induced mouse model of lung cancer and Akt isoform-specific knockout mice.</p><p>Results</p><p>Akt1 ablation significantly delays initiation of lung tumor growth, whereas Akt2 deficiency dramatically accelerates tumorigenesis in this mouse model. Ablation of Akt3 had a small, not statistically significant, stimulatory effect on tumor induction and growth by the viral oncogene. Terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling and Ki67 immunostaining of lung tissue sections revealed that the delayed tumor induction in Akt1^−/− mice was due to the inhibitory effects of Akt1 ablation on cell growth and survival. Conversely, the accelerated growth rate of lung tumors in Akt2^−/− and Akt3^−/− mice was due to increased cell proliferation and reduced tumor cell apoptosis. Investigation of Akt signaling in tumors from Akt knockout mice revealed that the lack of Akt1 interrupted the propagation of signaling in tumors to the critical downstream targets, GSK-3α/β and mTOR.</p><p>Conclusions</p><p>These results demonstrate that the degree of functional redundancy between Akt isoforms in the context of lung tumor initiation is minimal. Given that this mouse model exhibits considerable similarities to human lung cancer, these findings have important implications for the design and use of Akt inhibitors for the treatment of lung cancer.</p></div

Akt 1 is required for initiation and progression of lung tumors whereas Akt2 appears to be protective against tumorigenesis.

<p>Representative macroscopic images of individual lung lobes harvested from A_JEJJenv infected WT (A), Akt1^−/− (B), Akt2^−/− (C), and Akt3^−/− (D) mice as well as mock infected mice (E) at 20 weeks post-infection. Representative images of hematoxylin and eosin stained sections from the lungs of WT (F to H), Akt1^−/− (I to K), Akt2^−/− (L and M) and Akt3^−/− (N to P) mice infected with A_JEJJenv and harvested at 12, 20 and 32 weeks post-infection (4× magnification). Note that none of the Akt2^−/− infected mice survived past 20 weeks post-infection.</p

Lung tumors uniformly express Jenv and SPC irrespective of Akt isoform status.

<p>Immunostaining for Jenv, SPC, and CC10 expression in lung tissue from A_JEJJenv infected WT (A to C), Akt1^−/− (D to F), Akt2^−/− (G to I), and Akt3^−/− (J to L) mice at 10× magnification. Representative images of advanced neoplastic lesions show robust Jenv expression within all cells of the lung tumor (A, D, G, J). Representative images show lung tumors staining uniformly positive for SPC (B, E, H, K) and negative for CC10 (C, F, I, L).</p

Ablation of Akt2 dramatically enhances the initiation of lung tumorigenesis in A_JEJJenv infected mice.

<p>WT, Akt1^−/−, Akt2^−/− and Akt3^−/− mice infected with A_JEJJenv were euthanized at 12 (A), 20 (B) and 32 (C) weeks post infection and the number of lung tumors less than 100 μm, between 100 and 300 μm, and greater than 300 μm were quantified. Note that since all Akt2^−/− mice died around the 20-week time point there is no data for Akt2^−/− mice at the 32-week time point. Three lung lobes from three randomly selected mice per group were sectioned until the maximum surface area was exposed at which point all tumors within each lung lobe were counted. Bars on the graph labeled with an asterisk are statistically different (p<0.05).</p