https://escholarship.org/content/qt5st231s3/qt5st231s3.pdf?t=omsseb

Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy.

The Cancer Stem Cell Niche: How Essential Is the Niche in Regulating Stemness of Tumor Cells?

Tumor immune escape is an important strategy of tumor survival. There are many mechanisms of tumor immune escape, including immunosuppression, which has become a research hotspot in recent years. The programmed death ligand-1/programmed death-1 (PD-L1/PD-1) signaling pathway is an important component of tumor immunosuppression, which can inhibit the activation of T lymphocytes and enhance the immune tolerance of tumor cells, thereby achieving tumor immune escape. Therefore, targeting the PD-L1/PD-1 pathway is an attractive strategy for cancer treatment; however, the therapeutic effectiveness of PD-L1/PD-1 remains poor. This situation requires gaining a deeper understanding of the complex and varied molecular mechanisms and factors driving the expression and activation of the PD-L1/PD-1 signaling pathway. In this review, we summarize the regulation mechanisms of the PD-L1/PD-1 signaling pathway in the tumor microenvironment and their roles in mediating tumor escape. Overall, the evidence accumulated to date suggests that induction of PD-L1 by inflammatory factors in the tumor microenvironment may be one of the most important factors affecting the therapeutic efficiency of PD-L1/PD-1 blocking.

/pdf/role-of-the-tumor-microenvironment-in-pd-l1-pd-1-mediated-4cvw6htifn.pdf

Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape.

Fibroblasts regulate the structure and function of healthy tissues, participate transiently in tissue repair after acute inflammation, and assume an aberrant stimulatory role during chronic inflammatory states including cancer. Such cancer-associated fibroblasts (CAFs) modulate the tumor microenvironment and influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. These pleiotropic functions highlight the inherent plasticity of fibroblasts and may provide new avenues to understand and therapeutically intervene in malignancies. We discuss the emerging themes of CAF biology in the context of tumorigenesis and therapy.

/pdf/fibroblast-heterogeneity-in-the-cancer-wound-14jaxocpla.pdf

Fibroblast heterogeneity in the cancer wound

Cancer metastases: challenges and opportunities.

During tumor progression, circulating monocytes and macrophages are actively recruited into tumors where they alter the tumor microenvironment to accelerate tumor progression. Macrophages shift their functional phenotypes in response to various microenvironmental signals generated from tumor and stromal cells. Based on their function, macrophages are divided broadly into two categories: classical M1 and alternative M2 macrophages. The M1 macrophage is involved in the inflammatory response, pathogen clearance, and antitumor immunity. In contrast, the M2 macrophage influences an anti-inflammatory response, wound healing, and pro-tumorigenic properties. Tumor-associated macrophages (TAMs) closely resemble the M2-polarized macrophages and are critical modulators of the tumor microenvironment. Clinicopathological studies have suggested that TAM accumulation in tumors correlates with a poor clinical outcome. Consistent with that evidence, experimental and animal studies have supported the notion that TAMs can provide a favorable microenvironment to promote tumor development and progression. In this review article, we present an overview of mechanisms responsible for TAM recruitment and highlight the roles of TAMs in the regulation of tumor angiogenesis, invasion, metastasis, immunosuppression, and chemotherapeutic resistance. Finally, we discuss TAM-targeting therapy as a promising novel strategy for an indirect cancer therapy.

https://www.mdpi.com/2072-6694/6/3/1670/pdf

Tumor-associated macrophages as major players in the tumor microenvironment.

Excessive Hyaluronan Production Promotes Acquisition of Cancer Stem Cell Signatures through the Coordinated Regulation of Twist and the Transforming Growth Factor β (TGF-β)-Snail Signaling Axis *♦

Complex interactions between cancer cells and host stromal cells result in the formation of the “tumor microenvironment”, where inflammatory alterations involve the infiltration of tumor-associated fibroblasts and inflammatory leukocytes that contribute to the acquisition of malignant characteristics, such as increased cancer cell proliferation, invasiveness, metastasis, angiogenesis, and avoidance of adaptive immunity. The microenvironment of a solid tumor is comprised not only of cellular compartments, but also of bioactive substances, including cytokines, growth factors, and extracellular matrix (ECM). ECM can act as a scaffold for cell migration, a reservoir for cytokines and growth factors, and a signal through receptor binding. During inflammation, ECM components and their degraded fragments act directly and indirectly as inflammatory stimuli in certain cases and regulate the functions of inflammatory and immune cells. One such ECM component, hyaluronan, has recently been implicated to modulate innate immune cell function through pattern recognition toll-like receptors and accelerate the recruitment and activation of tumor-associated macrophages in inflamed cancers. Here, we will summarize the molecular mechanism linking inflammation with ECM remodeling in the tumor microenvironment, with a particular emphasis on the role of hyaluronan in controlling the inflammatory response.

https://www.mdpi.com/2072-6694/3/3/3189/pdf

Inflammatory Alterations of the Extracellular Matrix in the Tumor Microenvironment

Anesthesia strongly influences laboratory animals, and it can also greatly affect the experimental data. Rats rank only second to mice in the number used in research fields, such as organ transplantation, regenerative medicine and imaging. Therefore, appropriate and effective anesthesia, including the protocol of the endotracheal intubation and inhalation anesthesia, is crucial. Hence, we evaluated these methods in this study. Twelve Wistar rats were intraperitoneally injected with M/M/B: 0.3/4/5, comprising of medetomidine, midazolam and butorphanol at a dose of 0.3 mg/kg + 4.0 mg/kg + 5.0 mg/kg body weight/rat, respectively. An endotracheal tube was then intubated into the trachea. After intubation, the rats were connected to the inhalation anesthesia circuit using isoflurane, and vital signs were measured until 30 min after connection. All intubations were successfully finished within 1 min, and the values of the vital signs were normal and stable. In addition, histopathological observation of the trachea and lungs showed no trauma. These results suggest that this visible endotracheal intubation method is simple, reliable, safe and favorable with regard to the rats’ welfare.

Visible, safe and certain endotracheal intubation using endoscope system and inhalation anesthesia for rats.

Appropriate and effective anesthesia is critical, because it has a strong influence on laboratory animals, and its affect greatly impacts the experimental data. Inhalational anesthesia by endotracheal intubation is currently prevailing in general anesthesia and is prefered over injection anesthesia, especially for large laboratory animals, because it is a safe and easy control agent. However, it is not common for small laboratory animals, because of the high degree of technical skills required. We assessed the capability of use for mice of the endotracheal intubation by using the endoscope system “TESALA AE-C1” and inhalational anesthesia using a ventilator. Endotracheal intubation was successfully performed on all 10 C57BL/6 mice injected with M/M/B: 0.3/4/5 comprised of medetomidine, midazoram and butorphanol, at a dose of 0.3 mg/kg + 4.0 mg/kg + 5.0 mg/kg body weight/mouse, respectively. After the intubated mice were connected with the inhalational anesthesia circuit and the ventilator, vital signs were measured until 15 min after the connection. The data with M/M/B: 0.3/4/5 showed stable and normal values, which indicated that this new endotracheal intubation method was simple, reliable and safe, which mean that this anesthesia is favorable in regard to the animal’s welfare.

Kenjiro Konno

Papers

Tumor-associated macrophages as major players in the tumor microenvironment.

Excessive Hyaluronan Production Promotes Acquisition of Cancer Stem Cell Signatures through the Coordinated Regulation of Twist and the Transforming Growth Factor β (TGF-β)-Snail Signaling Axis *♦

Inflammatory Alterations of the Extracellular Matrix in the Tumor Microenvironment

Visible, safe and certain endotracheal intubation using endoscope system and inhalation anesthesia for rats.

New visible endotracheal intubation method using the endoscope system for mice inhalational anesthesia.