The CXCL12-CXCR4/CXCR7 axis as a mechanism of immune resistance in gastrointestinal malignancies

Publication date: Available online 23 December 2019Source: Seminars in Cancer BiologyAuthor(s): Sara K. Daniel, Y. Dave Seo, Venu G. PillarisettyAbstractSingle agent checkpoint inhibitor therapy has not been effective for most gastrointestinal solid tumors, but combination therapy with drugs targeting additional immunosuppressive pathways is being attempted. One such pathway, the CXCL12-CXCR4/CXCR7 chemokine axis, has attracted attention due to its effects on tumor cell survival and metastasis as well as immune cell migration. CXCL12 is a small protein that functions in normal hematopoietic stem cell homing in addition to repair of damaged tissue. Binding of CXCL12 to CXCR4 leads to activation of G protein signaling kinases such as P13 K/mTOR and MEK/ERK while binding to CXCR7 leads to β-arrestin mediated signaling. While some gastric and colorectal carcinoma cells have been shown to make CXCL12, the primary source in pancreatic cancer and peritoneal metastases is cancer-associated fibroblasts. Binding of CXCL12 to CXCR4 and CXCR7 on tumor cells leads to anti-apoptotic signaling through Bcl-2 and survivin upregulation, as well as promotion of the epithelial-to-mesechymal transition through the Rho-ROCK pathway and alterations in cell adhesion molecules. High levels of CXCL12 seen in the bone marrow, liver, and spleen could partially explain why these are popular sites of metastases for many tumors. CXCL12 is a chemoattractant for lymphocytes at lower levels, but b...
Source: Seminars in Cancer Biology - Category: Cancer & Oncology Source Type: research

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Authors: Nieder C, Dalhaug A, Haukland E Abstract Aim: The aim of this study was to evaluate the feasibility and efficacy, in terms of overall survival, of sequential systemic therapy in patients with metastatic castration-resistant prostate cancer (MCRPC) who lived in Nordland County, Norway, a large region with a challenging geography, yet only one department of oncology located in the main city, Bodø.Patients and methods: Overall 77 patients who had received at least 2 lines of treatment were included in this retrospective study.Results: Management included docetaxel in 69 patients (90%), often prescribed...
Source: Scandinavian Journal of Urology - Category: Urology & Nephrology Tags: Scand J Urol Source Type: research
Szpakowska M Abstract Chemokines regulate directed cell migration, proliferation and survival and are key components in cancer biology. They exert their functions by interacting with seven-transmembrane domain receptors that signal through G proteins (GPCRs). A subgroup of four chemokine receptors known as the atypical chemokine receptors (ACKRs) has emerged as essential regulators of the chemokine functions. ACKRs play diverse and complex roles in tumor biology from tumor initiation to metastasis, including cancer cell proliferation, adherence to endothelium, epithelial-mesenchymal transition (EMT), extravasatio...
Source: Advances in Cancer Research - Category: Cancer & Oncology Authors: Tags: Adv Cancer Res Source Type: research
Abstract As basic research into GPCR signaling and its association with disease has come into fruition, greater clarity has emerged with regards to how these receptors may be amenable to therapeutic intervention. As a diverse group of receptor proteins, which regulate a variety of intracellular signaling pathways, research in this area has been slow to yield tangible therapeutic agents for the treatment of a number of diseases including cancer. However, recently such research has gained momentum based on a series of studies that have sought to define GPCR proteins dynamics through the elucidation of their crystal ...
Source: Advances in Cancer Research - Category: Cancer & Oncology Authors: Tags: Adv Cancer Res Source Type: research
Abstract The G coupled protein receptor CC chemokine receptor type 5 (CCR5) has the unusual characteristic in humans of being a developmentally non-essential gene that participates in several pathological processes including infection with HIV (Dean et al., 1996; Gupta et al., 2019; Samson et al., 1996), progression of stroke (Joy et al., 2019), osteoporosis (Xie et al., 2019) and the metastasis of cancer (Jiao et al., 2018; Velasco-Velazquez et al., 2012, 2014) (Reviewed in: Jiao, Nawab, et al., 2019; Jiao, Wang, &Pestell, 2019). The importance of CCR5 in HIV led to recent genetic engineering of humans to rec...
Source: Advances in Cancer Research - Category: Cancer & Oncology Authors: Tags: Adv Cancer Res Source Type: research
Structure and function of β-arrestins, their emerging role in breast cancer, and potential opportunities for therapeutic manipulation. Adv Cancer Res. 2020;145:139-156 Authors: Shukla AK, Dwivedi-Agnihotri H Abstract β-Arrestins (βarrs) are multifunctional intracellular proteins with an ability to directly interact with a large number of cellular partners including the G protein-coupled receptors (GPCRs). βarrs contribute to multiple aspects of GPCR signaling, trafficking and downregulation. Considering the central involvement of GPCR signaling in the onset and progression of diver...
Source: Advances in Cancer Research - Category: Cancer & Oncology Authors: Tags: Adv Cancer Res Source Type: research
Abstract Atypical chemokine receptors (ACKRs) are seven-transmembrane cell surface protein receptors expressed in immune cells, normal mesenchymal cells, and several tumor cells. As of this writing, six ACKRs have been characterized by diverse activities. They bind both cysteine-cysteine (CC) type and cysteine-X-cysteine (CXC)-type chemokines, either alone, or together with a ligand bound-functional G-protein coupled (typical) chemokine receptor. The major structural difference between ACKRs and typical chemokine receptors is the substituted DRYLAIV amino acid motif in the second intracellular loop of the ACKR. Du...
Source: Advances in Cancer Research - Category: Cancer & Oncology Authors: Tags: Adv Cancer Res Source Type: research
Publication date: Available online 24 February 2020Source: Journal of the American College of RadiologyAuthor(s): Julianna M. Czum
Source: Journal of the American College of Radiology - Category: Radiology Source Type: research
This study included 114 patients with histologically confirmed PDAC who underwent contrast-enhanced CT and MRI before surgery. The tumor sizes from CT, MRI, and pathologic specimens were compared by using Bland –Altman analyses and intraclass correlation coefficients (ICCs). The discrepancies in PDAC size between CT/MRI and pathologic specimens were calculated and contributing factors for the discrepancies, including tumor locations (pancreatic head/neck, body, or tail), T stages (T1, T2, or T3), and N s tages (N0, N1, or N2), were analyzed with Pearson’s correlation coefficients and multivariable linear regres...
Source: Abdominal Imaging - Category: Radiology Source Type: research
ConclusionThere is a relatively low yield for detecting ureteral abnormalities when a retrograde pyelogram is performed after a CTU to evaluate an incompletely opacified ureteral segment —2.7% in our study, with only two of these incompletely opacified segments containing urothelial cancer (1.4%). In these two cases, a ureteral abnormality was visible on the CTU and RPG would seem to have a very low yield for follow up of unopacified ureteral segments if the ureters are otherwis e normal-appearing on CTU and there is no hydronephrosis.
Source: Abdominal Imaging - Category: Radiology Source Type: research
Genentech Inc. will pay $30 million upfront — and potentially $1.7 billion overall based on milestones — to work on a set of potential cancer immunotherapies with a British company. For Bicycle Therapeutics plc of Cambridge, England, and Lexington, Mass., the early discovery collaboration gives it a chance to show off its technology on m ore drugs that manipulate the immune system to spot and attack cancer cells. Specifically, Bicycle's appropriately named synthetic bicyclic peptides are designed…
Source: bizjournals.com Health Care:Pharmaceuticals headlines - Category: Pharmaceuticals Authors: Source Type: news
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