bims-stacyt 2023-01-22 papers

Cancers (Basel). 2023 Jan 06. pii: 376. [Epub ahead of print]15(2):

The Tumor Microenvironment in Tumorigenesis and Therapy Resistance Revisited.

Kevin Dzobo, Dimakatso A Senthebane, Collet Dandara.

Tumorigenesis is a complex and dynamic process involving cell-cell and cell-extracellular matrix (ECM) interactions that allow tumor cell growth, drug resistance and metastasis. This review provides an updated summary of the role played by the tumor microenvironment (TME) components and hypoxia in tumorigenesis, and highlight various ways through which tumor cells reprogram normal cells into phenotypes that are pro-tumorigenic, including cancer associated- fibroblasts, -macrophages and -endothelial cells. Tumor cells secrete numerous factors leading to the transformation of a previously anti-tumorigenic environment into a pro-tumorigenic environment. Once formed, solid tumors continue to interact with various stromal cells, including local and infiltrating fibroblasts, macrophages, mesenchymal stem cells, endothelial cells, pericytes, and secreted factors and the ECM within the tumor microenvironment (TME). The TME is key to tumorigenesis, drug response and treatment outcome. Importantly, stromal cells and secreted factors can initially be anti-tumorigenic, but over time promote tumorigenesis and induce therapy resistance. To counter hypoxia, increased angiogenesis leads to the formation of new vascular networks in order to actively promote and sustain tumor growth via the supply of oxygen and nutrients, whilst removing metabolic waste. Angiogenic vascular network formation aid in tumor cell metastatic dissemination. Successful tumor treatment and novel drug development require the identification and therapeutic targeting of pro-tumorigenic components of the TME including cancer-associated- fibroblasts (CAFs) and -macrophages (CAMs), hypoxia, blocking ECM-receptor interactions, in addition to the targeting of tumor cells. The reprogramming of stromal cells and the immune response to be anti-tumorigenic is key to therapeutic success. Lastly, this review highlights potential TME- and hypoxia-centered therapies under investigation.

Keywords: ECM; cancer hallmarks; drug resistance; exosomes; hypoxia; immune cells; stromal cells; targeted therapy; tumor microenvironment

DOI: https://doi.org/10.3390/cancers15020376

Int Immunopharmacol. 2023 Jan 09. pii: S1567-5769(23)00024-3. [Epub ahead of print]115 109701

Acute respiratory distress syndrome enhances tumor metastasis into lungs: Role of BRD4 in the tumor microenvironment.

Venkatesh Pooladanda, Sowjanya Thatikonda, Sai Priya Muvvala, Chandraiah Godugu.

Acute respiratory distress syndrome (ARDS) is associated with severe lung inflammation, edema, hypoxia, and high vascular permeability. The COVID-19-associated pandemic ARDS caused by SARS-CoV-2 has created dire global conditions and has been highly contagious. Chronic inflammatory disease enhances cancer cell proliferation, progression, and invasion. We investigated how acute lung inflammation activates the tumor microenvironment and enhances lung metastasis in LPS induced in vitro and in vivo models. Respiratory illness is mainly caused by cytokine storm, which further influences oxidative and nitrosative stress. The LPS-induced inflammatory cytokines made the conditions suitable for the tumor microenvironment in the lungs. In the present study, we observed that LPS induced the cytokine storm and promoted lung inflammation via BRD4, which further caused the nuclear translocation of p65 NF-κB and STAT3. The transcriptional activation additionally triggers the tumor microenvironment and lung metastasis. Thus, BRD4-regulated p65 and STAT3 transcriptional activity in ARDS enhances lung tumor metastasis. Moreover, LPS-induced ARDS might promote the tumor microenvironment and increase cancer metastasis into the lungs. Collectively, BRD4 plays a vital role in inflammation-mediated tumor metastasis and is found to be a diagnostic and molecular target in inflammation-associated cancers.

Keywords: BRD4; LPS; Lung inflammation; Tumor metastasis; p65 and STA3 nuclear translocation

DOI: https://doi.org/10.1016/j.intimp.2023.109701

Cells. 2023 Jan 12. pii: 292. [Epub ahead of print]12(2):

The Contribution of Tumor Derived Exosomes to Cancer Cachexia.

Christopher R Pitzer, Hector G Paez, Stephen E Alway.

Cancer cachexia is defined as unintentional weight loss secondary to neoplasia and is associated with poor prognosis and outcomes. Cancer cachexia associated weight loss affects both lean tissue (i.e., skeletal muscle) and adipose tissue. Exosomes are extracellular vesicles that originate from multivesicular bodies that contain intentionally loaded biomolecular cargo. Exosome cargo includes proteins, lipids, mitochondrial components, and nucleic acids. The cargo carried in exosomes is thought to alter cell signaling when it enters into recipient cells. Virtually every cell type secretes exosomes and exosomes are known to be present in nearly every biofluid. Exosomes alter muscle and adipose tissue metabolism and biological processes, including macrophage polarization and apoptosis which contribute to the development of the cachexia phenotype. This has led to an interest in the role of tumor cell derived exosomes and their potential role as biomarkers of cancer cell development as well as their contribution to cachexia and disease progression. In this review, we highlight published findings that have studied the effects of tumor derived exosomes (and extracellular vesicles) and their cargo on the progression of cancer cachexia. We will focus on the direct effects of tumor derived exosomes and their cellular cross talk on skeletal muscle and adipose tissue, the primary sites of weight loss due to cancer cachexia.

Keywords: adipocytes; adipose; cachexia; exosomes; extracellular vesicles; inflammation; metabolism; muscle

DOI: https://doi.org/10.3390/cells12020292

Brain Behav Immun. 2023 Jan 13. pii: S0889-1591(23)00005-3. [Epub ahead of print]

Perioperative escape from dormancy of spontaneous micro-metastases: A role for malignant secretion of IL-6, IL-8, and VEGF, through adrenergic and prostaglandin signaling.

Rita Haldar, Lee Shaashua Berger, Ella Rossenne, Arielle Radin, Anabel Eckerling, Elad Sandbank, Erica K Sloan, Steve W Cole, Shamgar Ben-Eliyahu.

We recently showed that a minimally-invasive removal of MDA-MB-231HM primary tumors (PTs) and elimination of their secreted factors (including IL-6, IL-8, VEGF, EGF, PDGF-aa, MIF, SerpinE1, and M-CSF), caused regression of spontaneous micro-metastases into a non-growing dormant state. To explore the underlying mechanisms and potential clinical ramifications of this phenomenon, we herein used the MDA-MB-231HM human breast cancer cell-line, in-vitro, and in vivo following orthotopic implantation in immune-deficient BALB/C nu/nu mice. Employing bioluminescence imaging, we found that adding laparotomy to minimally-invasive removal of the PT caused an outbreak of micro-metastases. However, perioperative β-adrenergic and COX-2 inhibition, using propranolol+etodolac, maintained metastatic dormancy following laparotomy. In-vitro, β-adrenergic agonists (epinephrine or metaproterenol) and prostaglandin-E2 markedly increased MDA-MB-231HM secretion of the pro-metastatic factors IL-6, IL-8, and VEGF, whereas cortisol reduced their secretion, effects that were maintained even 12h after the washout of these agonists. In-vivo, laparotomy elevated IL-6 and IL-8 levels in both plasma and ex-vivo PT spontaneous secretion, whereas perioperative propranolol+etodolac administration blocked these effects. Similar trends were evident for EGF and MIF. Promoter-based bioinformatics analyses of excised PT transcriptomes implicated elevated NF-kB activity and reduced IRF1 activity in the gene regulatory effects of laparotomy, and these effects were inhibited by pre-surgical propranolol+etodolac. Taken together, our findings suggest a novel mechanism of post-operative metastatic outbreak, where surgery-induced adrenergic and prostanoid signaling increase the secretion of pro-metastatic factors, including IL-6, IL-8, and VEGF, from PT and possibly residual malignant tissue, and thereby prevent residual disease from entering dormancy.

Keywords: Beta-adrenergic; Cancer; Dormancy; Etodolac; Inflammation; Metastasis; NSAID; Perioperative; Propranolol; Stress

DOI: https://doi.org/10.1016/j.bbi.2023.01.005

Eur J Med Res. 2023 Jan 19. 28(1): 37

Significant increase of serum extracellular vesicle-packaged growth differentiation factor 15 in type 2 diabetes mellitus: a cross-sectional study.

Wen Zhao, Xinwei Li, Xinxin Li, Lu Peng, Yu Li, Yunhui Du, Jianxun He, Yanwen Qin, Huina Zhang.

BACKGROUND: Growth differentiation factor 15 (GDF15) is a stress-inducible factor involved in the inflammatory progression of many complications, including type 2 diabetes mellitus (T2DM). Growing evidence suggests that molecules in extracellular vesicles (EVs) are associated with diabetes or diabetes-related complications. However, the correlation between serum extracellular vesicle-derived growth differentiation factor15 (EV-GDF15) and T2DM is unknown. The aim of this cross-sectional study is to investigate whether serum EV-GDF15 is associated with T2DM incidence.
METHODS: 116 individuals, including 78 T2DM and 38 non-T2DM, were recruited as participants. The concentrations of serum EV-GDF15 and serum GDF15 were determined by Luminex assay. Serum EVs were obtained by ultracentrifugation. Multivariate stepwise regression analysis was used to determine the association between serum GDF15 levels and fasting plasma glucose (FPG) as well as glycated hemoglobin (HbA1c). The association of serum EV-GDF15 levels with T2DM was determined by multivariate logistic regression analysis.
RESULTS: Our data showed that the levels of serum EV-GDF15 and serum GDF15 were significantly increased in T2DM patients compared with non-T2DM subjects (EV-GDF15 levels, 13.68 (6.61-23.44) pg/mL vs. 5.56 (3.44-12.09) pg/mL, P < 0.001; and serum GDF15 levels, 1025.49 (677.87-1626.36) pg/mL vs. 675.46 (469.53-919.98) pg/mL, P < 0.001). There was a linear correlation between EV-GDF15 levels and fasting plasma glucose (FPG) and Hemoglobin A1C (HbA1c) levels (normalized β = 0.357, P < 0.001; normalized β = 0.409, P < 0.001, respectively). Elevated levels of EV-GDF15 were accompanied by an increase in the proportion of patients with T2DM (from 47.5 to 78.9%) and a progressive independent association with the incidence of T2DM (from OR = 3.06, 95% CI 1.02-9.19, P = 0.047 to OR = 3.75, 95% CI 1.14-12.26, P = 0.029). Notably, high levels of serum GDF15 plus high levels of serum EV-GDF15 were significantly associated with T2DM more than either alone.
CONCLUSION: This study elucidated that increased levels of GDF15 in serum EVs were independently associated with T2DM.

Keywords: Biomarker; Extracellular vesicles; Growth differentiation factor 15; Serum; Type 2 diabetes mellitus

DOI: https://doi.org/10.1186/s40001-023-01009-6