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The complex and adaptive nature of malignant neoplasm constitute a major challenge for the development of effective anti-oncogenic therapies. Emerging evidence has uncovered the pivotal functions exerted by the small leucine-rich proteoglycans, decorin and biglycan, in affecting tumor growth and progression. In their soluble forms, decorin and biglycan act as powerful signaling molecules. By receptor-mediated signal transduction, both proteoglycans modulate key processes vital for tumor initiation and progression, such as autophagy, inflammation, cell-cycle, apoptosis, and angiogenesis. Despite of their structural homology, these two proteoglycans interact with distinct cell surface receptors and thus modulate distinct signaling pathways that ultimately affect cancer development. In this review, we summarize growing evidence for the complex roles of decorin and biglycan signaling in tumor biology and address potential novel therapeutic implications.
Highlights
• Deletion of SPPL3 promotes resistance of malignant B cells to NK cell cytotoxicity
• Loss of SPPL3 blocks ligand binding to NK receptors via increased N-glycosylation
• B3GNT2 deletion reduces LacNAc addition and restores SPPL3-KO cell sensitivity to NK cells
• SPPL3-deficient cells are enriched in tetra-antennary N-glycans with LacNAc elongations
Summary
Natural killer (NK) cells are primary defenders against cancer precursors, but cancer cells can persist by evading immune surveillance. To investigate the genetic mechanisms underlying this evasion, we perform a genome-wide CRISPR screen using B lymphoblastoid cells. SPPL3, a peptidase that cleaves glycosyltransferases in the Golgi, emerges as a top hit facilitating evasion from NK cytotoxicity. SPPL3-deleted cells accumulate glycosyltransferases and complex N-glycans, disrupting not only binding of ligands to NK receptors but also binding of rituximab, a CD20 antibody approved for treating B cell cancers. Notably, inhibiting N-glycan maturation restores receptor binding and sensitivity to NK cells. A secondary CRISPR screen in SPPL3-deficient cells identifies B3GNT2, a transferase-mediating poly-LacNAc extension, as crucial for resistance. Mass spectrometry confirms enrichment of N-glycans bearing poly-LacNAc upon SPPL3 loss. Collectively, our study shows the essential role of SPPL3 and poly-LacNAc in cancer immune evasion, suggesting a promising target for cancer treatment.
Activation of the tumor-associated stroma to support tumor growth is a common feature observed in different cancer entities. This principle is exemplified by cancer-associated fibroblasts (CAFs), which are educated by the tumor to shape its development across all stages. CAFs can alter the extracellular matrix (ECM) and secrete a variety of different molecules. In that manner they have the capability to affect activation, survival, proliferation, and migration of other stromal cells and cancer cell themselves. Alteration of the ECM, desmoplasia, is a common feature of breast cancer, indicating a prominent role for CAFs in shaping tumor development in the mammary gland. In this review, we summarize the multiple roles CAFs play in mammary carcinoma. We discuss experimental and clinical strategies to interfere with CAFs function in breast cancer. Moreover, we highlight the issues arising from CAFs heterogeneity and the need for further research to identify CAFs subpopulation(s) that can be targeted to improve breast cancer therapy.
The sphingolipid sphingosine-1-phosphate (S1P) promotes tumor development through a variety of mechanisms including promoting proliferation, survival, and migration of cancer cells. Moreover, S1P emerged as an important regulator of tumor microenvironmental cell function by modulating, among other mechanisms, tumor angiogenesis. Therefore, S1P was proposed as a target for anti-tumor therapy. The clinical success of current cancer immunotherapy suggests that future anti-tumor therapy needs to consider its impact on the tumor-associated immune system. Hereby, S1P may have divergent effects. On the one hand, S1P gradients control leukocyte trafficking throughout the body, which is clinically exploited to suppress auto-immune reactions. On the other hand, S1P promotes pro-tumor activation of a diverse range of immune cells. In this review, we summarize the current literature describing the role of S1P in tumor-associated immunity, and we discuss strategies for how to target S1P for anti-tumor therapy without causing immune paralysis.
MicroRNAs have been projected as promising tools for diagnostic and prognostic purposes in cancer. More recently, they have been highlighted as RNA therapeutic targets for cancer therapy. Though miRs perform a generic function of post-transcriptional gene regulation, their utility in RNA therapeutics mostly relies on their biochemical nature and their assembly with other macromolecules. Release of extracellular miRs is broadly categorized into two different compositions, namely exosomal (extracellular vesicles) and non-exosomal. This nature of miRs not only affects the uptake into target cells but also poses a challenge and opportunity for RNA therapeutics in cancer. By virtue of their ability to act as mediators of intercellular communication in the tumor microenvironment, extracellular miRs perform both, depending upon the target cell and target landscape, pro- and anti-tumor functions. Tumor-derived miRs mostly perform pro-tumor functions, whereas host cell- or stroma-derived miRs are involved in anti-tumor activities. This review deals with the recent understanding of exosomal and non-exosomal miRs in the tumor microenvironment, as a tool for pro- and anti-tumor activity and prospective exploit options for cancer therapy.
In this comprehensive review, we will dissect the impact of research on proteoglycans focusing on recent developments involved in their synthesis, degradation, and interactions, while critically assessing their usefulness in various biological processes. The emerging roles of proteoglycans in global infections, specifically the SARS-CoV-2 pandemic, and their rising functions in regenerative medicine and biomaterial science have significantly affected our current view of proteoglycans and related compounds. The roles of proteoglycans in cancer biology and their potential use as a next-generation protein-based adjuvant therapy to combat cancer is also emerging as a constructive and potentially beneficial therapeutic strategy. We will discuss the role of proteoglycans in selected and emerging areas of proteoglycan science, such as neurodegenerative diseases, autophagy, angiogenesis, cancer, infections and their impact on mammalian diseases.
Objective: Our aim was to explore whether general practitioners (GPs) communicate with cancer patients on complementary and integrative medicine (CIM) in a patient-centred and case-specific manner.
Methods: We designed two cases of standardised breast cancer patients and allocated 29 GPs to hold a consultation either with Case 1 or Case 2. Case 1 presented with fears of possible physical side effects of hormone treatment. Case 2 feared a loss in social functioning because of nausea and emesis as possible side effects of chemotherapy. Consultations were audiotaped and analysed using the Roter Interaction Analysis System (RIAS). We analysed whether recommended CIM treatments and GPs' focus on psychosocial or medical and therapy-related content differed according to whether they were counselling Case 1 or Case 2.
Results: In consultations with Case 1, GPs rather focused on medical and therapy-related content and most often recommended mistletoe, diets and sports. In contrast, GPs focused on psychosocial content and they most often recommended methods of self-care when counselling Case 2.
Conclusion: The GPs in our sample reacted case-specifically to the patients' interest in CIM. Such responsive and patient-centred communication is a valuable resource but is often time-consuming. Adequate training and reimbursement should therefore be considered for GPs.
Whereas the clinical approach in pediatric cancer patients with febrile neutropenia is well established, data on non-neutropenic infectious episodes are limited. We therefore prospectively collected over a period of 4 years of data on all infectious complications in children treated for acute lymphoblastic or myeloid leukemia (ALL or AML) and non-Hodgkin lymphoma (NHL) at two major pediatric cancer centers. Infections were categorized as fever of unknown origin (FUO), and microbiologically or clinically documented infections. A total of 210 patients (median age 6 years; 142 ALL, 23 AML, 38 NHL, 7 leukemia relapse) experienced a total of 776 infectious episodes (571 during neutropenia, 205 without neutropenia). The distribution of FUO, microbiologically and clinically documented infections, did not significantly differ between neutropenic and non-neutropenic episodes. In contrast to neutropenic patients, corticosteroids did not have an impact on the infectious risk in non-neutropenic children. All but one bloodstream infection in non-neutropenic patients were due to Gram-positive pathogens. Three patients died in the context of non-neutropenic infectious episodes (mortality 1.4%). Our results well help to inform clinical practice guidelines in pediatric non-neutropenic cancer patients presenting with fever, in their attempt to safely restrict broad-spectrum antibiotics and improve the quality of life by decreasing hospitalization.
Simple Summary: Infections are an important cause of morbidity and mortality in childhood cancer treatment. The aim of our retrospective study was to assess the infectious burden in pediatric sarcoma patients during neoadjuvant chemotherapy administered according to the EWING 2008, CWS SoTiSaR and EURAMOS clinical trial or registry. Our analyses indicate a substantial infectious morbidity in this group of patients, with 58.8% experiencing at least one episode of febrile neutropenia (FN) and 20.6% at least one microbiologically documented infection (MDI). We also identified parameters that impact on the occurrence of FN and MDIs, including treatment protocol, patient age, and mucositis. These findings may contribute to a better risk stratification for prevention and management of FN and infections as well as for maintaining quality of life, cost control, and optimum outcomes of anticancer treatment.
Abstract: The purpose of this retrospective, single-center cohort study was to assess the infectious burden in pediatric sarcoma patients during neoadjuvant chemotherapy. The review included all patients with a new diagnosis of Ewing sarcoma, osteosarcoma or soft tissue sarcoma between September 2009 and December 2018 who were enrolled in the EWING 2008, CWS SoTiSaR and EURAMOS clinical trial or registry. Primary endpoints were the occurrence of febrile neutropenia (FN) and microbiologically documented infection (MDI). Parameters with a potential impact on FN and MDI were also analyzed. A total of 170 sarcoma patients (median age: 13 years, range: 0–21; 96 m/74 f) received 948 chemotherapy courses (median: 6; range: 2–8). Of these patients, 58.8% had ≥1 FN episode and 20.6% ≥ 1 MDI. FN occurred in 272/948 courses (28.7%) with fever of unknown origin (FUO) in 231 courses and 45 MDI and 19 clinically documented infections (CDI) occurring in a total of 57 courses. Patients enrolled in EWING 2008 had significantly more FN (p < 0.001), infections (p = 0.02) and MDI (p = 0.035). No infection-related deaths were observed. Younger age, tumor type and localization, and higher median and maximum mucositis grades were significantly associated with higher numbers of FN (p < 0.001), and younger age (p = 0.024) and higher median mucositis grade (p = 0.017) with MDI. The study shows substantial infectious morbidity in sarcoma patients during neoadjuvant chemotherapy treatment and opportunities to improve prevention and management.
Despite the success of immune checkpoint blockade in cancer, the number of patients that benefit from this revolutionary treatment option remains low. Therefore, efforts are being undertaken to sensitize tumors for immune checkpoint blockade, which includes combining immune checkpoint blocking agents such as anti-PD-1 antibodies with standard of care treatments. Here we report that a combination of chemotherapy (doxorubicin) and immune checkpoint blockade (anti-PD-1 antibodies) induces superior tumor control compared to chemotherapy and immune checkpoint blockade alone in the murine autochthonous polyoma middle T oncogene-driven (PyMT) mammary tumor model. Using whole transcriptome analysis, we identified a set of genes that were upregulated specifically upon chemoimmunotherapy. This gene signature and, more specifically, a condensed four-gene signature predicted favorable survival of human mammary carcinoma patients in the METABRIC cohort. Moreover, PyMT tumors treated with chemoimmunotherapy contained higher levels of cytotoxic lymphocytes, particularly natural killer cells (NK cells). Gene set enrichment analysis and bead-based ELISA measurements revealed increased IL-27 production and signaling in PyMT tumors upon chemoimmunotherapy. Moreover, IL-27 signaling improved NK cell cytotoxicity against PyMT cells in vitro. Taken together, our data support recent clinical observations indicating a benefit of chemoimmunotherapy compared to monotherapy in breast cancer and suggest potential underlying mechanisms.