Development of PD-1 blockade peptide-cell conjugates to enhance cellular therapies for T-cell acute lymphoblastic leukemia.

Blockade of the interaction of the immune checkpoint receptor programmed cell death protein (PD)-1 and its ligand PD-L1 has been found to be a promising cancer treatment. Our previous studies identified that nABPD1 competed with PD-L1 to bind PD-1. The aim of this study was to evaluate the efficacy and safety of anti-tumor immunotherapy of ICIK cells conjugated with peptides in vivo and in vitro. Here, we synthesized the nABPD1 derivatives SBP1 and SBP2 and showed that their binding efficiency to PD-1-positive improving cytokine-induced killer (ICIK) cells was 98 and 82%, respectively. The cytotoxicity of ICIK cells to T-cell acute lymphoblastic leukemia (T-ALL) cells was increased by conjugating with SBP1 or SBP2, which was 2 times higher than that of ICIK cells alone. Furthermore, mice experiments showed that the fluorescence intensity of leukemia cells in T-ALL xenograft models was reduced by more than 95%, indicating that the peptides enhanced the therapeutic effect in vivo, while morphological evaluations showed that the peptides had no toxicity to important organs. Therefore, peptide-cell conjugates (PCCs) may be a novel method to improve the efficacy of cancer immunotherapy by blocking PD-1 in T-ALL patients.

Sox2 modulates motility and enhances progression of colorectal cancer via the Rho-ROCK signaling pathway.

Sox2 (Sry-box2) is essential for a variety of stem cells and is also expressed in colorectal cancer (CRC). However, the underlying mechanism by which Sox2 enhances CRC progression remains unclear. In the present study, we show that elevated Sox2 expression is significantly correlated with poor clinical prognosis. CRC is phenotypically heterogeneous, and harbors several subtypes of cancer cells. Elevated Sox2 expression was always detected in rounded-shape cells, which co-located to poorly differentiated regions, the invasive frontier and metastatic lesions. Knockdown of Sox2 in CRC cells not only decreased the number of round-shaped cells, but also suppressed cell migration, invasion as well as attenuated colony forming capacity and tumorigenicity. By contrast, overexpression of Sox2 in CRC cells was associated with up-regulation of multidrug resistance genes and accelerated CRC progression. Moreover, Sox2 conferred activation of Rho-ROCK signaling, whereas inhibition of ROCK signaling decreased cell migration, invasion, colony formation and self-renewal of CRC. Our results reveal that CRC is phenotypically and functionally heterogeneous. Elevated Sox2 expression activates the Rho-ROCK pathway, which in turn changes cell morphology and promotes cell migration and progression.

Decellularized tongue tissue as an in vitro model for studying tongue cancer and tongue regeneration.

The decellularization of tissues or organs provides an efficient strategy for preparing functional scaffolds for tissue engineering. The microstructures of native extracellular matrices and biochemical compositions retained in the decellularized matrices provide tissue-specific microenvironments for anchoring cells. Here, we report the tongue extracellular matrix (TEM), which showed favorable cytocompatibility for normal tongue-derived cells and tongue squamous cell carcinoma (TSCC) cells under static or stirring culture conditions. Our results show that TEM retained tongue-specific integrated microstructures and abundant matrix components, which offer mechanical support and spatial signals for regulating cell behavior and function. Reconstructed TSCC by TEM presented characteristics resembling clinical TSCC histopathology, suggesting the possibility for TSCC research. In addition, TEM might be capable of guiding tongue-derived cells to the niche, benefiting cell survival, proliferation and differentiation. STATEMENT OF SIGNIFICANCE: In this study, we prepared decellularized tongue extracellular matrix (TEM) and evaluated the possibility for tongue squamous cell carcinoma (TSCC) research and tongue regeneration. TEM has six irreplaceable advantages: (1) tongue-specific intricate structures of TEM, which offer mechanical support for the cells; (2) abundant matrix components and spatial signals benefiting for cell attachment, survival, differentiation, and long-term viability of the highly functional phenotypes of tongue cells or TSCC cells; (3) reconstructed TSCC by TEM exhibited tumor heterogeneity, extremely resembling clinical TSCC histopathology; (4) ideal model to evaluate TSCC movement mode; (5) guiding tongue-derived cells to the site-appropriate niche; and (6) the possibility for static or stirred cell culture. These properties might be considered in TSCC research or tongue regeneration.

Transforming growth factor ß1 signal is crucial for dedifferentiation of cancer cells to cancer stem cells in osteosarcoma.

Human osteosarcoma harbors a small subpopulation of cancer stem cells (CSCs) that is believed to be associated with tumor metastasis, radioresistance/chemoresistance, local invasion, and poor clinical outcome. In this study, we found that transforming growth factor ß1 (TGF-ß1) signaling and a hypoxic environment dramatically induced self-renewal capacity in non-stem osteosarcoma cells, which in turn promoted chemoresistance, tumorigenicity, neovasculogenesis, and metastatic potential. Furthermore, blocking the TGF-ß1 signaling pathway resulted in the inhibition of the dedifferentiation and clonogenicity of osteosarcoma cells, and the reduction of CSC self-renewal capacity and hypoxia-mediated dedifferentiation. These findings demonstrate that stem cells and non-stem cells exist in a dynamic equilibrium within the osteosarcoma cell population, and that CSCs may develop de novo from differentiated cancer cells. Hierarchical models of mammalian CSCs, therefore, should be considered to serve as bidirectional interconversion between the stem and non-stem cell components of the tumor.

Reactive oxygen species in cancer stem cells.

SIGNIFICANCE: Reactive oxygen species (ROS), byproducts of aerobic metabolism, are increased in many types of cancer cells. Increased endogenous ROS lead to adaptive changes and may play pivotal roles in tumorigenesis, metastasis, and resistance to radiation and chemotherapy. In contrast, the ROS generated by xenobiotics disturb the redox balance and may selectively kill cancer cells but spare normal cells. RECENT ADVANCES: Cancer stem cells (CSCs) are integral parts of pathophysiological mechanisms of tumor progression, metastasis, and chemo/radio resistance. Currently, intracellular ROS in CSCs is an active field of research. CRITICAL ISSUES: Normal stem cells such as hematopoietic stem cells reside in niches characterized by hypoxia and low ROS, both of which are critical for maintaining the potential for self-renewal and stemness. However, the roles of ROS in CSCs remain poorly understood. FUTURE DIRECTIONS: Based on the regulation of ROS levels in normal stem cells and CSCs, future research may evaluate the potential therapeutic application of ROS elevation by exogenous xenobiotics to eliminate CSCs.