bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2019‒12‒22
four papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge


  1. Cell Signal. 2019 Dec 17. pii: S0898-6568(19)30302-X. [Epub ahead of print] 109506
    Das NA, Carpenter AJ, Belenchia A, Aroor AR, Noda M, Siebenlist U, Chandrasekar B, DeMarco VG.
      BACKGROUND: Proximal tubular epithelial cells (PTEC) in the S1 segment of the kidney abundantly express sodium-glucose co-transporters (SGLT) that play a critical role in whole body glucose homeostasis. We recently reported suppression of RECK (Reversion Inducing Cysteine Rich Protein with Kazal Motifs), a membrane anchored endogenous MMP inhibitor and anti-fibrotic mediator, in the kidneys of db/db mice, a model of diabetic kidney disease (DKD), as well as in high glucose (HG) treated human kidney proximal tubule cells (HK-2). We further demonstrated that empagliflozin (EMPA), an SGLT2 inhibitor, reversed these effects. Little is known regarding the mechanisms underlying RECK suppression under hyperglycemic conditions, and its rescue by EMPA. Consistent with our previous studies, HG (25 mM) suppressed RECK expression in HK-2 cells. Further mechanistic investigations revealed that HG induced superoxide and hydrogen peroxide generation, oxidative stress-dependent TRAF3IP2 upregulation, NF-κB and p38 MAPK activation, inflammatory cytokine expression (IL-1β, IL-6, TNF-α, and MCP-1), miR-21 induction, MMP2 activation, and RECK suppression. Moreover, RECK gain-of-function inhibited HG-induced MMP2 activation and HK-2 cell migration. Similar to HG, advanced glycation end products (AGE) induced TRAF3IP2 and suppressed RECK, effects that were inhibited by EMPA. Importantly, EMPA treatment ameliorated all of these deleterious effects, and inhibited epithelial-to-mesenchymal transition (EMT) and HK-2 cell migration. Collectively, these findings indicate that hyperglycemia and associated AGE suppress RECK expression via oxidative stress/TRAF3IP2/NF-κB and p38 MAPK/miR-21 induction. Furthermore, these results suggest that interventions aimed at restoring RECK or inhibiting SGLT2 have the potential to treat kidney inflammatory response/fibrosis and nephropathy under chronic hyperglycemic conditions, such as DKD.
    Keywords:  Diabetic kidney disease; Fibrosis; Inflammation; SGLT2
    DOI:  https://doi.org/10.1016/j.cellsig.2019.109506
  2. Cancer Res. 2019 Dec 17. pii: canres.2013.2019. [Epub ahead of print]
    Jing B, Wang T, Sun B, Xu J, Xu D, Liao Y, Song H, Guo W, Li K, Hu M, Zhang S, Ling J, Kuang Y, Zhang T, Zhou BP, Yao F, Deng J.
      Cancer cells that succeed in forming metastasis need to be reprogrammed to evade immune surveillance and survive in a new microenvironment. This is facilitated by metastatic niches that are either post-formed through reciprocal signaling between tumor cells and local stromal cells or pre-formed as pre-metastatic niches before tumor cell arrival. IL-6/STAT3 signaling is aberrantly activated in lung tumorigenesis and metastasis, however, the roles and mechanisms of action of IL-6 remain controversial. Here, we showed that blockade of intrinsic STAT3 signaling in lung tumor cells suppressed lung metastasis in immune-competent syngeneic mice, but not in immune-deficient nude mice. Consistently, repression of STAT3 signaling in tumor cells made them susceptible to T cell-mediated cytotoxicity. Thus, STAT3-mediated immunosuppression is crucial for metastasis. Noticeably, lung metastasis was greatly increased in Gprc5a-knockout (ko) (5a-/-) mice compared to wild-type (WT) mice, which correlated with upregulated IL-6 in the tumor microenvironment. Depletion of IL-6 via combined deletion of Il6 and Gprc5a genes almost completely eliminated lung metastasis in Gprc5a-ko/Il-6-ko (5a-/-;Il6-/-) mice. Mechanistically, dysregulated IL-6 reprogrammed the STAT3 pathway in metastatic tumor cells, and induced recruitment of myeloid-derived suppressor cells and polarized macrophages to evade host immunity. Consistently, immunohistochemistry staining showed that activated STAT3 correlated with repressed infiltration CD8+ T cells in non-small cell lung cancer. Therefore, IL-6/STAT3 signaling is crucial for orchestrating pre-metastatic niche formation and immunosuppression in the lung.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-2013
  3. Cancers (Basel). 2019 Dec 20. pii: E29. [Epub ahead of print]12(1):
    Huang JY, Wang YY, Lo S, Tseng LM, Chen DR, Wu YC, Hou MF, Yuan SF.
      Adipose-derived stem cells (ADSCs) have been implicated in tumor growth and metastasis in breast cancer. ADSCs exhibit tumor tropism, and are of increasing clinical relevance due to the autologous fat grafting for breast reconstruction. Although we have previously shown that a high level of the adipocytokine visfatin in human breast cancer tissues correlated with tumor progression mediated by cAbl and STAT3, the effects of visfatin in the tumor microenvironment are unclear. To understand how visfatin modulates breast cancer within the tumor-stromal environment, we examined determinants of breast cancer progression using a visfatin-primed ADSCs-tumor co-culture model. ADSCs were isolated from tumor-free adipose tissue adjacent to breast tumors. ADSCs were treated with or without visfatin for 48 h and then collected for co-culture with breast cancer cell line MDA-MB-231 for 72 h in a transwell system. We found that the MDA-MB-231 cells co-cultured with visfatin-treated ADSCs (vADSCs) had higher levels of cell viability, anchorage independent growth, migration, invasion, and tumorsphere formation than that co-cultured with untreated ADSCs (uADSCs). Growth differentiation factor 15 (GDF15) upregulation was found in the co-culture conditioned medium, with GDF15 neutralizing antibody blocking the promoting effect on MDA-MB-231 in co-culture. In addition, a GDF15-induced AKT pathway was found in MDA-MB-231 and treatment with PI3K/AKT inhibitor also reversed the promoting effect. In an orthotopic xenograft mouse model, MDA-MB-231 co-injected with vADSCs formed a larger tumor mass than with uADSCs. Positive correlations were noted between visfatin, GDF15, and phosphor-AKT expressions in human breast cancer specimens. In conclusion, visfatin activated GDF15-AKT pathway mediated via ADSCs to facilitate breast cancer progression.
    Keywords:  GDF15; adipose-derived stem cells (ADSCs); breast cancer; visfatin
    DOI:  https://doi.org/10.3390/cancers12010029
  4. Cell Rep. 2019 Dec 17. pii: S2211-1247(19)31570-0. [Epub ahead of print]29(12): 4086-4098.e6
    Hart PC, Kenny HA, Grassl N, Watters KM, Litchfield LM, Coscia F, Blaženović I, Ploetzky L, Fiehn O, Mann M, Lengyel E, Romero IL.
      The tumor microenvironment (TME) plays a pivotal role in cancer progression, and, in ovarian cancer (OvCa), the primary TME is the omentum. Here, we show that the diabetes drug metformin alters mesothelial cells in the omental microenvironment. Metformin interrupts bidirectional signaling between tumor and mesothelial cells by blocking OvCa cell TGF-β signaling and mesothelial cell production of CCL2 and IL-8. Inhibition of tumor-stromal crosstalk by metformin is caused by the reduced expression of the tricarboxylic acid (TCA) enzyme succinyl CoA ligase (SUCLG2). Through repressing this TCA enzyme and its metabolite, succinate, metformin activated prolyl hydroxylases (PHDs), resulting in the degradation of hypoxia-inducible factor 1α (HIF1α) in mesothelial cells. Disruption of HIF1α-driven IL-8 signaling in mesothelial cells by metformin results in reduced OvCa invasion in an organotypic 3D model. These findings indicate that tumor-promoting signaling between mesothelial and OvCa cells in the TME can be targeted using metformin.
    Keywords:  HIF1; IL-8; SUCLG2; TGF; mesothelial cells; metformin; omental metastasis; ovarian cancer; succinate; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2019.11.079