Archives

  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • 2021-03
  • The underlying mechanism of breast cancer metastasis from

    2019-07-24

    The underlying mechanism of breast cancer metastasis from the primary tumor to the bone is a very complex and remains to be fully elucidated [3]. The contribution of the primary tumor microenvironment to malignant progression plays a very important role [[44], [45], [46]]. Our animal model was designed with breast cancer-induced bone destruction as the final outcome and not as a model for the malignant metastasis of the primary mammary tissues to the distant skeletal system. We recognize this as a limitation of the study and therefore it is impossible to fully assess the direct effect of SREBP-2 inhibition therapy on breast cancer metastases to bone. None-the-less, we found that targeted inhibition of SREBP-2 with Fatostatin can protect against breast cancer-induced osteolysis by inhibiting osteoclast formation and activity. Furthermore, tumor size in the bone was also significantly reduced with lower expressions of SREBP-2 and MMPs. The following are the supplementary data related to this article.
    Transparency document
    Introduction Obesity is a major contributing factor to the rising incidence of type-2 diabetes and metabolic syndrome. Obesity is associated with low-grade, chronic inflammation. Compartmentalized immune response in metabolic tissues participates in some aspects of metabolic defects during obesity, including insulin resistance, hyperlipidemia, and hepatic steatosis [[1], [2], [3], [4], [5]]. Adipose tissue captures some of the nutrient excess during obesity and the resultant adipose tissue expansion is associated with increased inflammation and augmented lipolysis in adipocytes. The source of inflammation in specific tissues during obesity is still poorly defined. Obesity is associated with altered taxonomy and predicted function of the intestinal microbial composition [6]. There is evidence of metabolic disease factors such as age, dysglycemia and diet influencing microbial load and amount of specific bacterial components that penetrating into metabolic tissues [[7], [8], [9]]. Recognition of these microbial cues by pathogen sensing system can contribute to obesity-induced inflammation [10,11]. Pattern recognition receptors (PRRs) of the innate immune system are part of pathogen sensing system that recognize the pathogen-associated molecular patterns (PAMPs) and activate signaling cascades leading to propagation of inflammatory response [12]. Two prominent Fulvestrant (ICI 182,780) of PRRs are membrane-anchored Toll-like receptors (TLRs) that predominantly recognize pathogen derived insults in extracellular or endosomal compartments, and cytosolic nucleotide oligomerization domain-like receptors (NLRs) that sense intracellular pathogen derived insults and perturbations associated with stress response or tissue damage [12]. Nod1 and Nod2 are best characterized members of NLR family that are intracellular sensors for bacterial peptidoglycan (PGN) and induce pro-inflammatory response upon recognition of specific PGN ligand [13]. The minimal PGN moiety recognized by Nod1 is d-glutamyl-meso-diaminopimelic acid (meso-DAP), found mainly in Gram-negative bacteria, whereas Nod2 detects muramyl dipeptide (MDP) containing PGN motif that are commonly found in both Gram-positive and Gram-negative bacterial strains [14,15]. Well characterized immune responses engaged by Nod1 and Nod2 signaling such as those through NF-κB have already been associated with obesity-associated inflammation and specific metabolic disturbances. Despite the fact that Nod2 can induce muscle cell autonomous inflammation and insulin resistance [16,17], the effects on whole body glucose control are very different. It is known that deletion of Nod2 worsens diet-induced dysglycemia and the administration of postbiotics that activate Nod2 are insulin Fulvestrant (ICI 182,780) sensitizers [18]. In general, Nod1 has the opposite effects of Nod2 on glucose metabolism. We have previously showed that Nod1 activation can induce whole body and cell-autonomous insulin resistance [19]. Acute activation of Nod1 triggers inflammation and insulin resistance in liver and adipose tissue in vivo and Nod1 deficient mice are protected from high fed diet (HFD)-induced adiposity and glucose intolerance [19,20]. Moreover, exposure to HFD increases circulating level of Nod1 activator in mice, implicating the involvement of Nod1 in induction of metabolic inflammation [21]. In adipocytes, PGN-induced activation of Nod1 has been shown to suppress their differentiation [22] and to promote pro-inflammatory response and insulin resistance [23]. Moreover, Nod1 activation in adipocytes is associated with induction of lipolysis through activation of, NF-κB, ERK, and PKA [24,25]. Induction of lipolysis can further promote adipocytes inflammation through stress kinases [26], contributing to induction of insulin resistance. However, the association of Nod1-mediated lipolysis with induction of inflammation is not completely defined. It was not known if Nod1-mediated lipolysis can lead to inflammation through cell autonomous accumulation of lipid intermediates.