Abstract
Cancer development is highly associated to the physiological state of the tumor microenvironment (TME). Despite the existing heterogeneity of tumors from the same or from different anatomical locations, common features can be found in the TME maturation of epithelial-derived tumors. Genetic alterations in tumor cells result in hyperplasia, uncontrolled growth, resistance to apoptosis, and metabolic shift towards anaerobic glycolysis (Warburg effect). These events create hypoxia, oxidative stress and acidosis within the TME triggering an adjustment of the extracellular matrix (ECM), a response from neighbor stromal cells (e.g., fibroblasts) and immune cells (lymphocytes and macrophages), inducing angiogenesis and, ultimately, resulting in metastasis. Exosomes secreted by TME cells are central players in all these events. The TME profile is preponderant on prognosis and impacts efficacy of anti-cancer therapies. Hence, a big effort has been made to develop new therapeutic strategies towards a more efficient targeting of TME. These efforts focus on: (i) therapeutic strategies targeting TME components, extending from conventional therapeutics, to combined therapies and nanomedicines; and (ii) the development of models that accurately resemble the TME for bench investigations, including tumor-tissue explants, “tumor on a chip” or multicellular tumor-spheroids.
Highlights
The development of effective anti-cancer therapies has been challenged by the overall complexity of tumors [1,2,3]
The lower activity of prolyl-hydroxylase enzyme-2 (PHD-2) allows the translocation of HIF-1α to the nucleus, interacting with the HIF-1β subunit and, together with the transcriptional co-activators P300 and CREB binding protein (CBP), binds to the hypoxia-responsive elements located at the promoter regions of over 100 genes involved in hypoxia response [19,44]
Monocytes, originated in bone marrow and spleen, are recruited to tumors by both malignant stromal or tumor cell-derived chemokines and growth factors, and can differentiate in two subsets of macrophages, the M1-type macrophages that are activated by interferon gamma (IFN-γ), and the M2-type macrophages that are induced by exposure to cytokines, such as interleukin 4 (IL-4), IL-10, transforming growth factor-β (TGF-β), Ggranulocyte-macrophage colony stimulating factor (GM-CSF), Aannexin A1, or tumor cell-surface molecules [73,74,75]
Summary
The development of effective anti-cancer therapies has been challenged by the overall complexity of tumors [1,2,3]. The tumor heterogeneity is exacerbated during the progression of the cancer along with the maturation of the cellular and noncellular components of the tumor niche—the tumor microenvironment (TME) [4,5]. As tumor cells continue proliferation, the tumor increases in size with an associated remodeling of the TME. This is induced by hypoxia, oxidative stress and acidosis, due to an alteration of tumor cells metabolism, resulting in dysplasia, which is the appearance of a heterogeneous population of tumoral cells with. Sci. 2019, 20, x different genetic and phenotypic traits [10,11] These events are orchestrated by autocrine and paanradcprianreaccroinmemcoumnmicautnioicnastiownisthwsithrosmtraolmcaelllcealnl danidmimmunuenesyssytsetmemaaddjajacceennttttoo the ttuummoorr,,ccoouuppleledd totoaannininccrreeaasseeddinintteerrssttiittiiaallflfluuiiddpprreessssuurree[[88,,1111]]. TohfeTsMtudEydoufrTinMgEtduumroinrgdteuvmeolorpdmeveenltopremveenatls prreovgenaolsstipcrbogionmosatrikcebrsiotmhaatrkmearsy tbheaut smedayfobreimuasegdingfoor rimfoargliiqnugidorbifoopr slyiqaunidalybsioisp, sbyotahniamlypsoisr,tabnotthto seimlepctotrhtaenmt otostsseuleitcatbtlehethmeroasptys(urietvaibelwe ethdeirnap[1y3–(1re5v])i.ewTheids rienv[ie1w3–1su5]m).mTahriiszersevthieewcusrurmenmt kanriozwesletdhgee ocnutrhreenmt kanjoorwplleadygeerso/nevtheentms ainjovroplvlaeyderins/eTvMenEtsminatvuorlavteidoninofTtMheE pmriamtuarraytiotunmoof rththeaptrcimanariyndtuumceoorr dtihsarut pctancanincderucperoogrredsissirounp.tAcdandciteironparlolyg,rewsesiodnis.cAusdsdtihtieornaaplelyu,tiwc estrdaitsecguisess tahregraeptienugtitchesstreaetevgeinetss, frtoamrgestianngdtahrdesceuervrentst,hferroampesuttaicnsdtaordnacnuormreendt itchinerea-bpaesuetdicsaptoprnoaanchomeseadnidcinfuet-ubaresemdeathpopdrosatcohmesoannitdor thfuetTuMreEmienthvoitdros .to monitor the TME in vitro
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