Tumor-associated macrophages: from mechanisms to therapy.

Tissues with defined cellular hierarchies in development and homeostasis give rise to tumors with cellular hierarchies, suggesting that tumors recapitulate specific tissues and mimic their origins. Glioblastoma (GBM) is the most prevalent and malignant primary brain tumor and contains self-renewing, tumorigenic cancer stem cells (CSCs) that contribute to tumor initiation and therapeutic resistance. As normal stem and progenitor cells participate in tissue development and repair, these developmental programs re-emerge in CSCs to support the development and progressive growth of tumors. Elucidation of the molecular mechanisms that govern CSCs has informed the development of novel targeted therapeutics for GBM and other brain cancers. CSCs are not self-autonomous units; rather, they function within an ecological system, both actively remodeling the microenvironment and receiving critical maintenance cues from their niches. To fulfill the future goal of developing novel therapies to collapse CSC dynamics, drawing parallels to other normal and pathological states that are highly interactive with their microenvironments and that use developmental signaling pathways will be beneficial.

/pdf/cancer-stem-cells-in-glioblastoma-56rj4maz9b.pdf

Cancer stem cells in glioblastoma

The Microenvironmental Landscape of Brain Tumors

There is a growing recognition that gliomas are complex tumors composed of neoplastic and non-neoplastic cells, which each individually contribute to cancer formation, progression and response to treatment. The majority of the non-neoplastic cells are tumor-associated macrophages (TAMs), either of peripheral origin or representing brain-intrinsic microglia, that create a supportive stroma for neoplastic cell expansion and invasion. TAMs are recruited to the glioma environment, have immune functions, and can release a wide array of growth factors and cytokines in response to those factors produced by cancer cells. In this manner, TAMs facilitate tumor proliferation, survival and migration. Through such iterative interactions, a unique tumor ecosystem is established, which offers new opportunities for therapeutic targeting.

/pdf/the-role-of-microglia-and-macrophages-in-glioma-maintenance-2s2re941kn.pdf

The role of microglia and macrophages in glioma maintenance and progression

Glioblastomas (GBM) are one of the most recalcitrant brain tumors because of their aggressive invasive growth and resistance to therapy. They are highly heterogeneous malignancies at both the molecular and histological levels. Specific histological hallmarks including pseudopalisading necrosis and microvascular proliferation distinguish GBM from lower-grade gliomas, and make GBM one of the most hypoxic as well as angiogenic tumors. These microanatomical compartments present specific niches within the tumor microenvironment that regulate metabolic needs, immune surveillance, survival, invasion as well as cancer stem cell maintenance. Here we review features and functions of the distinct GBM niches, detail the different cell constituents and the functional status of the vasculature, and discuss prospects of therapeutically targeting GBM niche constituents.

Glioblastoma: Defining Tumor Niches

Brain tumor initiating cells (BTICs) contribute to the genesis and recurrence of gliomas. We examined whether the microglia and macrophages that are abundant in gliomas alter BTIC growth. We found that microglia derived from non-glioma human subjects markedly mitigated the sphere-forming capacity of glioma patient-derived BTICs in culture by inducing the expression of genes that control cell cycle arrest and differentiation. This sphere-reducing effect was mimicked by macrophages, but not by neurons or astrocytes. Using a drug screen, we validated amphotericin B (AmpB) as an activator of monocytoid cells and found that AmpB enhanced the microglial reduction of BTIC spheres. In mice harboring intracranial mouse or patient-derived BTICs, daily systemic treatment with non-toxic doses of AmpB substantially prolonged life. Notably, microglia and monocytes cultured from glioma patients were inefficient at reducing the sphere-forming capacity of autologous BTICs, but this was rectified by AmpB. These results provide new insights into the treatment of gliomas.

Therapeutic activation of macrophages and microglia to suppress brain tumor-initiating cells

Circular saws are widely used in wood processing for applications ranging from primary lumber manufacturing to furniture industry and home workshops. They directly contribute to production problems...

Active Vibration Control with State Feedback in Woodcutting

Glioblastoma is a ferociously expanding form of tumor with a grim prognosis even after surgical removal.  The tumor most frequently returns after surgery, which may point to a population of cells that have the capacity to initiate a relapse. Resident macrophage population of the brain should tame tumor growth but glioma seems to be interfering with their normal response hence growing even in their presence. Artificial activation of macrophages has been shown to decelerate the growth of glioma in mouse model. doi : 10.5214/ans.0972.7531.200407

/pdf/therapeutic-activation-of-macrophages-and-microglia-to-3rthtio4zz.pdf

Therapeutic activation of macrophages and microglia to suppress brain tumor-initiating cells.

This paper discusses the development and setup of an infrastructure for real-time monitoring and control of industrial processes or machines remotely through the Internet. The main philosophy behind this approach is the use of a single web-server, which is connected to multiple industrial processes in a specific cluster. The Web-server pools all real-time information from the processes and distributes relevant information to remote users who are logged on to workstations called virtual project stations. A remote user is also able to control the local process through the Web-server. Live audio and video signals are streamed to the remote users enabling them to view the physical setup and behavior of the process. This Web-based monitoring and control strategy is particularly useful when applied to industrial processes such as wood-drying kilns. Specifically, several kilns may be monitored and controlled simultaneously from a centralized engineering operation, or anywhere in the world. Efficient round-the-clock production is then possible.

Monitoring and control of a wood-drying kiln via virtual project stations

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Therapeutic activation of macrophages and microglia to suppress brain tumor-initiating cells

Active Vibration Control with State Feedback in Woodcutting

Therapeutic activation of macrophages and microglia to suppress brain tumor-initiating cells.

Monitoring and control of a wood-drying kiln via virtual project stations