Chemokines Modulate Immune Surveillance in Tumorigenesis, Metastasis, and Response to Immunotherapy

Chemokines are small secreted proteins that orchestrate migration and positioning of immune cells within the tissues. Chemokines are essential for the function of the immune system. Accumulating evidence suggest that chemokines play important roles in tumor microenvironment. In this review we discuss an association of chemokine expression and activity within the tumor microenvironment with cancer outcome. We summarize regulation of immune cell recruitment into the tumor by chemokine-chemokine receptor interactions and describe evidence implicating chemokines in promotion of the “inflamed” immune-cell enriched tumor microenvironment. We review both tumor-promoting function of chemokines, such as regulation of tumor metastasis, and beneficial chemokine roles, including stimulation of anti-tumor immunity and response to immunotherapy. Finally, we discuss the therapeutic strategies target tumor-promoting chemokines or induce/deliver beneficial chemokines within the tumor focusing on pre-clinical studies and clinical trials going forward. The goal of this review is to provide insight into comprehensive role of chemokines and their receptors in tumor pathobiology and treatment

Interactions of the p53 protein family in cellular stress response in gastrointestinal tumors

p53, p63 and p73 are members of the p53 protein family involved in regulation of cell cycle, apoptosis, differentiation and other critical cellular processes. Here we investigated the contribution of the entire p53 family in chemotherapeutic drug response in gastrointestinal tumors. Real-time PCR and immunohistochemistry revealed complexity and variability of expression profiles of the p53 protein family. Using colon and esophageal cancer cells, we found that the integral transcription activity of the entire p53 family, as measured by the reporter analysis, associated with response to drug treatment in studied cells. We also found that p53 and p73, as well as p63 and p73, bind simultaneously to the promoters of p53 target genes. Taken together, our results support the view that the p53 protein family functions as an interacting network of proteins and show that cellular responses to chemotherapeutic drug treatment are determined by the total activity of the entire p53 family, rather than p53 alone

Preparation of (−)-Nutlin‑3 Using Enantioselective Organocatalysis at Decagram Scale

Chiral nonracemic <i>cis</i>-4,5-bis­(aryl)­imidazolines have emerged as a powerful platform for the development of cancer chemotherapeutics, stimulated by the Hoffmann-La Roche discovery that Nutlin-3 can restore apoptosis in cells with wild-type p53. The lack of efficient methods for the enantioselective synthesis of <i>cis</i>-imidazolines, however, has limited their more general use. Our disclosure of the first enantioselective synthesis of (−)-Nutlin-3 provided a basis to prepare larger amounts of this tool used widely in cancer biology. Key to the decagram-scale synthesis described here was the discovery of a novel bis­(amidine) organocatalyst that provides high enantioselectivity at warmer reaction temperature (−20 °C) and low catalyst loadings. Further refinements to the procedure led to the synthesis of (−)-Nutlin-3 in a 17 g batch and elimination of all but three chromatographic purifications

Characterization of ΔNp73 expression and regulation in gastric and esophageal tumors

p73 is a member of the p53 protein family. Although the tumor suppressor function of p53 is clearly defined, the role of p73 in tumorigenesis is still a matter of debate. A complex pattern of expression of p73 isoforms makes it difficult to unambiguously interpret the experimental results. Previously, we and others have found that the N-terminally truncated isoform of p73, ΔNp73, has potent anti-apoptotic and oncogenic properties in vitro and in vivo . In the present study, we analyzed, for the first time, the regulation of ΔNp73 in a large number of gastric, gastroesophageal junction and esophageal tumors. We found that expression of ΔNp73 mRNA and protein is increased in these neoplasms. Furthermore, the up-regulation of the ΔNp73 protein is significantly associated with poor patient survival. Oncogenic properties of ΔNp73 were further confirmed by finding that ΔNp73 facilitates anchorage-independent growth of gastric epithelial cells in soft agar. As little is currently known about the regulation of ΔNp73 transcription, we investigated the alternative p73 gene promoter that mediates the ΔNp73 expression. Analyzing the ΔNp73 promoter in silico as well as by using chromatin immunoprecipitation, site-directed mutagenesis and deletion analyses we identified the evolutionary conserved region within the ΔNp73 promoter that contains binding sites for HIC1 protein. We found that HIC1 negatively regulates ΔNp73 transcription in mucosal epithelial cells. This leads to a decrease in ΔNp73 protein levels and may normally control the oncogenic potential of the ΔNp73 isoform

Obtaining patient-derived cancer organoid cultures via fine-needle aspiration

Patient-derived tumor organoid cultures are an essential and innovative methodology for translational research. However, current techniques to establish these cultures are cumbersome, expensive, and often require irreplaceable clinical tissue from surgery or core biopsies. Fine-needle aspiration (FNA) provides a minimally invasive biopsy technique commonly performed in clinical settings. Here, we provide a protocol for FNA. We have found that FNA provides a cost-effective, rapid, and streamlined method for tissue acquisition for cancer organoid culture. For complete details on the use and execution of this protocol, please refer to Lee et al. (2020) and Vilgelm et al. (2020). [Display omitted] •Fine-needle aspiration (FNA) to obtain patient-derived organoid cultures•FNA offers a cost-effective and minimally invasive method to obtain tissue•FNA-based organoid cultures can be used for many downstream applications Patient-derived tumor organoid cultures are an essential and innovative methodology for translational research. However, current techniques to establish these cultures are cumbersome, expensive, and often require irreplaceable clinical tissue from surgery or core biopsies. Fine-needle aspiration (FNA) provides a minimally invasive biopsy technique commonly performed in clinical settings. Here, we provide a protocol for FNA. We have found that FNA provides a cost-effective, rapid, and streamlined method for tissue acquisition for cancer organoid culture