bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2021‒02‒28
seven papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

  1. Mol Cancer Res. 2021 Feb 22. pii: molcanres.0403.2020. [Epub ahead of print]
      Placental growth factor (PlGF) is a pro-angiogenic, N-glycosylated growth factor, which is secreted under pathological situations. Here, we investigated the regulation of PlGF in response to ionizing radiation (IR) and its role for tumor angiogenesis and radiosensitivity. Secretion and expression of PlGF was induced in multiple tumor cell lines (medulloblastoma, colon and lung adenocarcinoma) in response to irradiation in a dose- and time-dependent manner. Early upregulation of PlGF expression and secretion in response to irradiation was primarily observed in p53 wildtype tumor cells, whereas tumor cells with mutated p53 only showed a minimal or delayed response. Mechanistic investigations with genetic and pharmacological targeting of p53 corroborated regulation of PlGF by the tumor suppressor p53 in response to irradiation under normoxic and hypoxic conditions, but with so far unresolved mechanisms relevant for its minimal and delayed expression in tumor cells with a p53-mutated genetic background. Probing a paracrine role of IR-induced PlGF secretion in vitro, migration of endothelial cells was specifically increased towards irradiated PlGF wildtype but not towards irradiated PlGF knockout medulloblastoma cells. Tumors derived from these PlGF-ko cells displayed a reduced growth rate, but similar tumor vasculature formation as in their wildtype counterparts. Interestingly though, high-dose irradiation strongly reduced microvessel density with a concomitant high rate of complete tumor regression only in the PlGF-ko tumors. Implications: Our study shows a strong paracrine vasculature-protective role of PlGF as part of a p53-regulated IR-induced resistance mechanism and suggest PlGF as a promising target for a combined treatment modality with RT.
  2. J Cell Mol Med. 2021 Feb 23.
      Pathologic angiogenesis directly responds to tumour hypoxia and controls the molecular/cellular composition of the tumour microenvironment, increasing both immune tolerance and stromal cooperation with tumour growth. Myo-inositol-trispyrophosphate (ITPP) provides a means to achieve stable normalization of angiogenesis. ITPP increases intratumour oxygen tension (pO2 ) and stabilizes vessel normalization through activation of endothelial Phosphatase-and-Tensin-homologue (PTEN). Here, we show that the tumour reduction due to the ITPP-induced modification of the tumour microenvironment by elevating pO2 affects the phenotype and properties of the immune infiltrate. Our main observations are as follows: a relative change in the M1 and M2 macrophage-type proportions, increased proportions of NK and CD8+ T cells, and a reduction in Tregs and Th2 cells. We also found, in vivo and in vitro, that the impaired access of PD1+ NK cells to tumour cells is due to their adhesion to PD-L1+ /PD-L2+ endothelial cells in hypoxia. ITPP treatment strongly reduced PD-L1/PD-L2 expression on CD45+/CD31+ cells, and PD1+ cells were more numerous in the tumour mass. CTLA-4+ cell numbers were stable, but level of expression decreased. Similarly, CD47+ cells and expression were reduced. Consequently, angiogenesis normalization induced by ITPP is the mean to revert immunosuppression into an antitumor immune response. This brings a key adjuvant effect to improve the efficacy of chemo/radio/immunotherapeutic strategies for cancer treatment.
    Keywords:  angiogenesis; cancer; hypoxia; immune response; microenvironment; myo-inositol trispyrophosphate; oxygen partial pressure (pO2); vessel normalization
  3. J Biol Chem. 2021 Feb 19. pii: S0021-9258(21)00213-1. [Epub ahead of print] 100440
      Obesity associates with inflammation, insulin resistance and higher blood lipids. It is unclear if immune responses facilitate lipid breakdown and release from adipocytes via lipolysis in a separate way from hormones or adrenergic signals. We found that an ancient component of ER stress, inositol-requiring protein 1 (IRE1), discriminates inflammation-induced adipocyte lipolysis versus lipolysis from adrenergic or hormonal stimuli. Our data show that inhibiting IRE1 kinase activity was sufficient to block adipocyte-autonomous lipolysis from multiple inflammatory ligands, including bacterial components, certain cytokines, and thapsigargin-induced ER stress. IRE1-mediated lipolysis was specific for inflammatory triggers since IRE1 kinase activity was dispensable for isoproterenol and cAMP-induced lipolysis in adipocytes and mouse adipose tissue. IRE1 RNase activity was not associated with inflammation-induced adipocyte lipolysis. Inhibiting IRE1 kinase activity blocked NF-κB activation, interleukin-6 secretion, and adipocyte-autonomous lipolysis from inflammatory ligands. Inflammation-induced lipolysis mediated by IRE1 occurred independently from changes in insulin signaling in adipocytes, suggesting that inflammation can promote IRE1-mediated lipolysis independent of adipocyte insulin resistance. We found no role for canonical unfolded protein responses or ABL kinases in linking ER stress to IRE1-mediated lipolysis. Adiponectin-Cre-mediated IRE1 knockout in mice showed that adipocyte IRE1 was required for inflammatory ligand-induced lipolysis in adipose tissue explants and that adipocyte IRE1 was required for approximately half of the increase in blood triglycerides after a bacterial endotoxin-mediated inflammatory stimulus in vivo. Together, our results show that IRE1 propagates an inflammation-specific lipolytic program independent from hormonal or adrenergic regulation. Targeting IRE1 kinase activity may benefit metabolic syndrome and inflammatory lipid disorders.
    Keywords:  ER stress; adipocyte; cytokine; endocrinology; immunometabolism; inflammation; lipid; lipolysis; metabolic syndrome; obesity
  4. Anal Chem. 2021 Feb 26.
      It is increasingly recognized that the cellular microenvironment plays critical roles in regulating the fate and physiology of cells. Despite recent advancements in single-cell analysis technologies, engineering and integration of the microenvironment for single-cell analysis platforms remain limited. Here, we report a single-cell cytokine secretion analysis platform that integrated both the three-dimensional cell culture and the primary oral squamous cell carcinoma tumor cell co-culture to provide both physical and physiological cues for single cells to be analyzed. We apply the platform to investigate the immune responses of human macrophages stimulated with the ligand of toll-like receptor 4 lipopolysaccharide. Notably, we observe the differential modulation effect in cytokine secretions by the tumor microenvironment, in which antitumor cytokine TNF-a secretion was attenuated, and protumor cytokine IL-6 would increase. The differential modulation effect is conserved from cell line-derived macrophages to primary macrophages derived from healthy donors. Immunofluorescence staining further reveals that ∼50% of macrophage cells could be polarized from M1 to the M2 phenotype within 12 h in the engineered tumor microenvironment. This work demonstrates the significance of the cell microenvironment toward single-cell analysis, which could help to evaluate how immune cells will respond in the complex microenvironment more accurately.
  5. Obesity (Silver Spring). 2021 Feb 22.
      Obesity is a risk factor for developing several cancers. The dysfunctional metabolism and chronic activation of inflammatory pathways in obesity create a milieu that supports tumor initiation, progression, and metastasis. Obesity-associated metabolic, endocrine, and inflammatory mediators, besides interacting with cells leading to a malignant transformation, also modify the intrinsic metabolic and functional characteristics of immune myeloid cells. Here, the evidence supporting the hypothesis that obesity metabolically primes and promotes the expansion of myeloid cells with immunosuppressive and pro-oncogenic properties is discussed. In consequence, the accumulation of these cells, such as myeloid-derived suppressor cells and some subtypes of adipose-tissue macrophages, creates a microenvironment conducive to tumor development. In this review, the role of lipids, insulin, and leptin, which are dysregulated in obesity, is emphasized, as well as dietary nutrients in metabolic reprogramming of these myeloid cells. Moreover, emerging evidence indicating that obesity enhances immunotherapy response and hypothesized mechanisms are summarized. Priorities in deeper exploration involving the mechanisms of cross talk between metabolic disorders and myeloid cells related to cancer risk in patients with obesity are highlighted.
  6. Mol Cancer Ther. 2021 Feb 25. pii: molcanther.MCT-20-0699-A.2020. [Epub ahead of print]
      This study shows that pancreatic cancer cells undergoing cell death by Valproic Acid (VPA) treatment activated DCs more efficiently than those treated with Trichostatin A (TSA), as demonstrated by CD86 and CD80 surface expression. Surprisingly though, DCs cultured in the presence of supernatant derived from VPA-treated cancer cells showed a reduced allostimulatory capacity and an increased release of IL-10 and IL-8 cytokines in comparison to those exposed to TSA-treated cells culture supernatant. Searching for molecular mechanisms leading to such differences, we found that VPA treatment dysregulated choline metabolism and triggered a stronger ER stress in pancreatic cancer cells than TSA, up-regulating CHOP, and activated COX2, thus promoting the release of prostaglandin (PG) E2. Interestingly, dysfunctional DCs cultured in the presence of VPA-treated cells culture supernatant showed a higher level of intracellular ROS, 4-HNE protein adducts and ER stress, as evidenced by the up-regulation of spliced XBP1 (XBP1s), effects that were reduced when DCs were exposed to supernatant of cancer cells treated with Celecoxib before VPA. Celecoxib indeed prevented PGE2 release, restoring the function of DCs exposed to VPA-treated cells culture supernatant and a similar effect was obtained by silencing XBP1s in DCs treated with VPA-treated cells culture supernatant. These results suggest that PGE2 could be one of the yet unidentified factors able to transfer the stress from cancer cells to DCs, resulting in an impairment of their function.
  7. Expert Rev Proteomics. 2021 Feb 22.
      INTRODUCTION: Proteins are responsible for all cellular behaviors and activities and also play a key role in disease progression. Proteomics can be an effective tool for identifying diagnostic and therapeutic biomarkers for lung cancer. Cytokines are proteins that play a decisive role in activating the body's immune system in lung cancer. They can increase the growth of the tumor (oncogenic cytokines) or limit tumor growth (anti-tumor cytokines) by regulating related signaling pathways such as proliferation, growth, invasion, differentiation, migration, metastasis, and apoptosis.AREAS COVERED: In the present study, a total of 220 papers including 193 research papers and 27 review papers, extracted from PubMed and Scopus and published from 1997 to present, are reviewed. The most important cytokines involved in lung cancer are introduced, including: TNF-α, IFN-γ, TGF-β, VEGF and several interleukins such as IL-6, IL-17, IL-8, IL-10, IL-22, IL-1β and IL-18. Also, the pathological and biological role of such cytokines in cancer signaling pathways is explained. Moreover, the samples and different proteomic techniques used for the evaluation and identification of cancer markers and proteomes such as cytokines are summarized.
    EXPERT OPINION: In lung cancer, the rate of cytokine expression changes under the physiological conditions of the immune system, and inflammatory cytokines are associated with the progression of lung cancer. Therefore, the cytokine expression profile can be used in the diagnosis, prognosis, prediction of therapeutic responses, and survival of patients with lung cancer.
    Keywords:  Proteomics; biomarker; cytokine; expression; lung cancer