Thrombospondins and remodeling of the tumor microenvironment

Vascular remodeling defines cancer growth and aggressiveness. Although cancer cells produce pro-angiogenic signals, the fate of angiogenesis critically depends on the cancer microenvironment. Composition of the extracellular matrix (ECM) and tumor inflammation determine whether a cancer will remain dormant, will be recognized by the immune system and eliminated, or whether the tumor will develop and lead to the spread and metastasis of cancer cells. Thrombospondins (TSPs), a family of ECM proteins that has long been associated with the regulation of angiogenesis and cancer, regulate multiple physiological processes that determine cancer growth and spreading, from angiogenesis to inflammation, metabolic changes, and properties of ECM. Here, we sought to review publications that describe various functions of TSPs that link these proteins to regulation of cancer growth by modulating multiple physiological and pathological events that prevent or support tumor development. In addition to its direct effects on angiogenesis, TSPs have important roles in regulation of inflammation, immunity, ECM properties and composition, and glucose and insulin metabolism. Furthermore, TSPs have distinct roles as regulators of remodeling in tissues and tumors, such that the pathways activated by a single TSP can interact and influence each other. The complex nature of TSP interactions and functions, including their different cell- and tissue-specific effects, may lead to confusing results and controversial conclusions when taken out of the context of interdisciplinary and holistic approaches. However, studies of TSP functions and roles in different systems of the organism offer an integrative view of tumor remodeling and a potential for finding therapeutic targets that would modulate multiple complementary processes associated with cancer growth

Adolescent Intermittent Alcohol Exposure: Dysregulation of Thrombospondins and Synapse Formation are Associated with Decreased Neuronal Density in the Adult Hippocampus

Background: Adolescent intermittent alcohol exposure (AIE) has profound effects on neuronal function. We have previously shown that AIE causes aberrant hippocampal structure and function that persists into adulthood. However, the possible contributions of astrocytes and their signaling factors remain largely unexplored. We investigated the acute and enduring effects of AIE on astrocytic reactivity and signaling on synaptic expression in the hippocampus, including the impact of the thrombospondin (TSP) family of astrocyte‐secreted synaptogenic factors and their neuronal receptor, alpha2delta‐1 (α2δ‐1). Our hypothesis is that some of the influences of AIE on neuronal function may be secondary to direct effects on astrocytes. Methods: We conducted Western blot analysis on TSPs 1 to 4 and α2δ‐1 from whole hippocampal lysates 24 hours after the 4th and 10th doses of AIE, then 24 days after the last dose (in adulthood). We used immunohistochemistry to assess astrocyte reactivity (i.e., morphology) and synaptogenesis (i.e., colocalization of pre‐ and postsynaptic puncta). Results: Adolescent AIE reduced α2δ‐1 expression, and colocalized pre‐ and postsynaptic puncta after the fourth ethanol (EtOH) dose. By the 10th dose, increased TSP2 levels were accompanied by an increase in colocalized pre‐ and postsynaptic puncta, while α2δ‐1 returned to control levels. Twenty‐four days after the last EtOH dose (i.e., adulthood), TSP2, TSP4, and α2δ‐1 expression were all elevated. Astrocyte reactivity, indicated by increased astrocytic volume and area, was also observed at that time. Conclusions: Repeated EtOH exposure during adolescence results in long‐term changes in specific astrocyte signaling proteins and their neuronal synaptogenic receptor. Continued signaling by these traditionally developmental factors in adulthood may represent a compensatory mechanism whereby astrocytes reopen the synaptogenic window and repair lost connectivity, and consequently contribute to the enduring maladaptive structural and functional abnormalities previously observed in the hippocampus after AIE