bims-stacyt 2023-04-30 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2023–04–30
seven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Extracellular vesicles released during hypoxia transport heparanase and enhance macrophage migration, endothelial tube formation and cancer cell stemness.
Acidity promotes the differentiation of immunosuppressive regulatory T cells.
Hypoxia induces downregulation of the tumor-suppressive sST2 in colorectal cancer cells via the HIF-nuclear IL-33-GATA3 pathway.
Tumor loss-of-function mutations in STK11/LKB1 induce cachexia.
Significance of localized expression of full-length growth differentiation factor-15 in cachexia of advanced non-small cell lung cancer.
Targeting leukemia inhibitory factor in pancreatic adenocarcinoma.
Cachexia: A systemic consequence of progressive, unresolved disease.

Proteoglycan Res. 2023 Jan 01. pii: e1. [Epub ahead of print]1(1):

Extracellular vesicles released during hypoxia transport heparanase and enhance macrophage migration, endothelial tube formation and cancer cell stemness.

Kaushlendra Tripathi, Shyam K Bandari, Ralph D Sanderson.

  Heparanase is upregulated during the progression of most cancers and via its enzyme activity promotes extracellular matrix degradation, angiogenesis and cell migration. Heparanase expression is often associated with enhanced tumor aggressiveness and chemoresistance. We previously demonstrated that increased heparanase expression in tumor cells enhances secretion and alters the composition of tumor-released exosomes. In the present study, we discovered that extracellular vesicles (EVs) secreted by human multiple myeloma cells growing in hypoxic conditions exhibited elevated levels of heparanase cargo compared to EVs from cells growing in normoxic conditions. When macrophages (RAW 264.7 monocyte/macrophage-like cells) were exposed to EVs released by tumor cells growing in either hypoxic or normoxic conditions, macrophage migration and invasion was elevated by EVs from hypoxic conditions. The elevated invasion of macrophages was blocked by a monoclonal antibody that inhibits heparanase enzyme activity. Moreover, the heparanase-bearing EVs from hypoxic cells greatly enhanced endothelial cell tube formation consistent with the known role of heparanase in promoting angiogenesis. EVs from hypoxic tumor cells when compared with EVs from normoxic cells also enhanced cancer stemness properties of both CAG and RPMI 8226 human myeloma cells. Together these data indicate that under hypoxic conditions, tumor cells secrete EVs having an elevated level of heparanase as cargo. These EVs can act on both tumor and non-tumor cells, enhancing tumor progression and tumor cell stemness that likely supports chemoresistance and relapse of tumor.

Keywords:  exosome; heparanase; hypoxia; macrophages; myeloma; stem cells; tumor

DOI:  https://doi.org/10.1002/pgr2.1
Eur J Immunol. 2023 Apr 25. e2350511

Acidity promotes the differentiation of immunosuppressive regulatory T cells.

Karoliina Tuomela, Megan K Levings.

  The metabolic milieu is emerging as a major contributing factor in the maintenance of the immunosuppressive microenvironment within tumours. In particular, the presence of lactic acid produced by highly glycolytic cancer cells is known to suppress antitumour immune cell subsets while promoting immunosuppressive cell populations, such as regulatory T cells (Tregs). Unlike conventional T cells, Tregs have a uniquely potent ability to take up lactic acid to fuel both mitochondrial metabolism and gluconeogenesis, supporting suppressive function and proliferation. In this issue of the European Journal of [Immunology [Eur. J. Immunol. 2023.53:2250258], Rao et al. uncover a novel mechanism by which lactic acid can support Treg accumulation within tumours in mice. This study shows that lactic acid, through a pH-dependent mechanism rather than lactate itself, promotes TGFβ-induced differentiation of Tregs from conventional CD4+ T cells. These findings build on the already multifaceted role of lactic acid in maintaining an immunosuppressive tumour microenvironment. This article is protected by copyright. All rights reserved.

Keywords:  Lactic acid; Regulatory T cells; Treg metabolism; immunosuppressive microenvironment

DOI:  https://doi.org/10.1002/eji.202350511
Proc Natl Acad Sci U S A. 2023 May 02. 120(18): e2218033120

Hypoxia induces downregulation of the tumor-suppressive sST2 in colorectal cancer cells via the HIF-nuclear IL-33-GATA3 pathway.

Miho Akimoto, Takao Susa, Noriyuki Okudaira, Nobuko Koshikawa, Harumi Hisaki, Masayoshi Iizuka, Hiroko Okinaga, Keizo Takenaga, Tomoki Okazaki, Mimi Tamamori-Adachi.

  As a decoy receptor, soluble ST2 (sST2) interferes with the function of the inflammatory cytokine interleukin (IL)-33. Decreased sST2 expression in colorectal cancer (CRC) cells promotes tumor growth via IL-33-mediated bioprocesses in the tumor microenvironment. In this study, we discovered that hypoxia reduced sST2 expression in CRC cells and explored the associated molecular mechanisms, including the expression of key regulators of ST2 gene transcription in hypoxic CRC cells. In addition, the effect of the recovery of sST2 expression in hypoxic tumor regions on malignant progression was investigated using mouse CRC cells engineered to express sST2 in response to hypoxia. Our results indicated that hypoxia-dependent increases in nuclear IL-33 interfered with the transactivation activity of GATA3 for ST2 gene transcription. Most importantly, hypoxia-responsive sST2 restoration in hypoxic tumor regions corrected the inflammatory microenvironment and suppressed tumor growth and lung metastasis. These results indicate that strategies targeting sST2 in hypoxic tumor regions could be effective for treating malignant CRC.

Keywords:  colorectal cancer; hypoxia; interleukin-33; metastasis; soluble ST2

DOI:  https://doi.org/10.1073/pnas.2218033120
JCI Insight. 2023 Apr 24. pii: e165419. [Epub ahead of print]8(8):

Tumor loss-of-function mutations in STK11/LKB1 induce cachexia.

Puneeth Iyengar, Aakash Y Gandhi, Jorge Granados, Tong Guo, Arun Gupta, Jinhai Yu, Ernesto M Llano, Faya Zhang, Ang Gao, Asha Kandathil, Dorothy Williams, Boning Gao, Luc Girard, Venkat S Malladi, John M Shelton, Bret M Evers, Raquibul Hannan, Chul Ahn, John D Minna, Rodney E Infante.

  Cancer cachexia (CC), a wasting syndrome of muscle and adipose tissue resulting in weight loss, is observed in 50% of patients with solid tumors. Management of CC is limited by the absence of biomarkers and knowledge of molecules that drive its phenotype. To identify such molecules, we injected 54 human non-small cell lung cancer (NSCLC) lines into immunodeficient mice, 17 of which produced an unambiguous phenotype of cachexia or non-cachexia. Whole-exome sequencing revealed that 8 of 10 cachexia lines, but none of the non-cachexia lines, possessed mutations in serine/threonine kinase 11 (STK11/LKB1), a regulator of nutrient sensor AMPK. Silencing of STK11/LKB1 in human NSCLC and murine colorectal carcinoma lines conferred a cachexia phenotype after cell transplantation into immunodeficient (human NSCLC) and immunocompetent (murine colorectal carcinoma) models. This host wasting was associated with an alteration in the immune cell repertoire of the tumor microenvironments that led to increases in local mRNA expression and serum levels of CC-associated cytokines. Mutational analysis of circulating tumor DNA from patients with NSCLC identified 89% concordance between STK11/LKB1 mutations and weight loss at cancer diagnosis. The current data provide evidence that tumor STK11/LKB1 loss of function is a driver of CC, simultaneously serving as a genetic biomarker for this wasting syndrome.

Keywords:  Genetic variation; Lung cancer; Metabolism; Molecular genetics; Oncology

DOI:  https://doi.org/10.1172/jci.insight.165419
Support Care Cancer. 2023 Apr 28. 31(5): 308

Significance of localized expression of full-length growth differentiation factor-15 in cachexia of advanced non-small cell lung cancer.

Satomi Morita-Tanaka, Aya Miyagawa-Hayashino, Tadaaki Yamada, Yohei Matsui, Kenji Morimoto, Osamu Hiranuma, Naoko Masuzawa, Akihiro Yoshimura, Masahiro Iwasaku, Shinsaku Tokuda, Yoshiko Kaneko, Young Hak Kim, Eiichi Konishi, Koichi Takayama.

   PURPOSE: Growth differentiation factor-15 (GDF-15) is one of the key cachexia-inducing factors. Clinical trials on therapies targeting GDF-15 for cancer and cancer cachexia are underway. While the role of circulating GDF-15 in cachexia has been clarified, the effects of GDF-15 expression within cancer cells remain to be fully elucidated. Hence, the objective of this study was to investigate the expression of GDF-15 in advanced lung cancer tissues and to understand its role in cachexia.
METHODS: We retrospectively examined the expression level of full-length GDF-15 in advanced non-small cell lung cancer tissues and analyzed the relationship between the staining intensity and clinical data in 53 samples.
RESULTS: We found that 52.8% of the total samples were GDF-15 positive, and GDF-15 expression significantly correlated with improved C-reactive protein/albumin ratio (p = 0.008). It did not correlate with the existence of cancer cachexia and overall survival (p = 0.43).
CONCLUSION: Our findings show that GDF-15 expression significantly correlated with improved C-reactive protein/albumin ratio, but not the existence of cancer cachexia in advanced NSCLC patients.

Keywords:  Advanced non-small cell lung carcinoma; C-reactive protein/albumin ratio; Growth differentiation factor-15; Immunohistochemistry

DOI:  https://doi.org/10.1007/s00520-023-07771-x
Expert Opin Investig Drugs. 2023 Apr 24. 1-13

Targeting leukemia inhibitory factor in pancreatic adenocarcinoma.

Jing Wang, Christian Karime, Umair Majeed, Jason S Starr, Mitesh J Borad, Hani M Babiker.

   INTRODUCTION: The Leukemia Inhibitory Factor (LIF) is a member of the interleukin-6 (IL-6) cytokine family. Known to induce differentiation of myeloid leukemia cells, evidence has accumulated supporting its role in cancer evolution through regulating cell differentiation, renewal, and survival. LIF has recently emerged as a biomarker and therapeutic target for pancreatic ductal adenocarcinoma (PDAC). The first in-human clinical trial has shown promising safety profile and has suggested a potential role for LIF inhibitor in combination regimen.
AREAS COVERED: Herein, we summarize, discuss, and give an expert opinion on the role of LIF in PDAC promotion, and its potential role as a biomarker and target of anti-cancer therapy. We conducted an exhaustive PubMed search for English-language articles published from 1 January 1970, to 1 August 2022.
EXPERT OPINION: PDAC carries a devastating prognosis for patients, highlighting the need for advancing drug development. The results of the phase 1 trial with MSC-1 demonstrated tolerability and safety but modest efficacy. Future research should focus on investigating LIF targets in combination with current standard-of-care chemotherapy, and immunotherapy can be a promising approach. Further, larger multicenter clinical trials are needed to define the use of LIF as a new biomarker in PDAC patients.

Keywords:  EC359; Leukemia inhibitory factor; MSC-1; biomarker; pancreatic ductal adenocarcinoma; therapeutic target; tumor microencironment

DOI:  https://doi.org/10.1080/13543784.2023.2206558
Cell. 2023 Apr 27. pii: S0092-8674(23)00325-2. [Epub ahead of print]186(9): 1824-1845

Cachexia: A systemic consequence of progressive, unresolved disease.

Miriam Ferrer, Tracy G Anthony, Janelle S Ayres, Giulia Biffi, Justin C Brown, Bette J Caan, Elizabeth M Cespedes Feliciano, Anthony P Coll, Richard F Dunne, Marcus D Goncalves, Jonas Grethlein, Steven B Heymsfield, Sheng Hui, Mariam Jamal-Hanjani, Jie Min Lam, David Y Lewis, David McCandlish, Karen M Mustian, Stephen O'Rahilly, Norbert Perrimon, Eileen P White, Tobias Janowitz.

Cachexia, a systemic wasting condition, is considered a late consequence of diseases, including cancer, organ failure, or infections, and contributes to significant morbidity and mortality. The induction process and mechanistic progression of cachexia are incompletely understood. Refocusing academic efforts away from advanced cachexia to the etiology of cachexia may enable discoveries of new therapeutic approaches. Here, we review drivers, mechanisms, organismal predispositions, evidence for multi-organ interaction, model systems, clinical research, trials, and care provision from early onset to late cachexia. Evidence is emerging that distinct inflammatory, metabolic, and neuro-modulatory drivers can initiate processes that ultimately converge on advanced cachexia.

DOI: https://doi.org/10.1016/j.cell.2023.03.028