1、Contents lists available at ScienceDirectSeminars in Cancer Biologyjournal homepage: of the tumor microenvironment by natural agents:implicationsfor cancer prevention and therapyHaseeb Zubaira,b,1,2,Mohammad Aslam Khana,b,2,Shashi Ananda,b,Sanjeev Kumar Srivastavaa,b,Seema Singha,b,c,Ajay Pratap Sin
2、gha,b,c,*aDepartment of Pathology,College of Medicine,University of South Alabama,Mobile,AL,USAbMitchell Cancer Institute,University of South Alabama,Mobile,AL,USAcDepartment of Biochemistry and Molecular Biology,College of Medicine,University of South Alabama,Mobile,AL,USAA R T I C L E I N F OKeywo
3、rds:Tumor microenvironmentNatural productsChemopreventionTherapeutic targetingPhytochemicalMarine-based agentsA B S T R A C TThe development of cancer is not just the growth and proliferation of a single transformed cell,but its sur-rounding environment also coevolves with it.Indeed,successful cance
4、r progression depends on the ability of thetumor cells to develop a supportive tumor microenvironment consisting of various types of stromal cells.Theinteractions between the tumor and stromal cells are bidirectional and mediated through a variety of growthfactors,cytokines,metabolites,and other bio
5、molecules secreted by these cells.Tumor-stromal crosstalk createsoptimal conditions for the tumor growth,metastasis,evasion of immune surveillance,and therapy resistance,and its targeting is being explored for clinical management of cancer.Natural agents from plants and marine lifehave been at the f
6、orefront of traditional medicine.Numerous epidemiological studies have reported the healthbenefits imparted on the consumption of certain fruits,vegetables,and their derived products.Indeed,a sig-nificant majority of anti-cancer drugs in clinical use are either naturally occurring compounds or their
7、 deriva-tives.In this review,we describe fundamental cellular and non-cellular components of the tumor micro-environment and discuss the significance of natural compounds in their targeting.Existing literature provideshope that novel prevention and therapeutic approaches will emerge from ongoing sci
8、entific efforts leading to thereduced tumor burden and improve clinical outcomes in cancer patients.1.IntroductionCancer is one of the significant causes of death,affecting millions ofpeople globally.About 1,806,590 new cancer diagnoses and nearly606,520 cancer-related deaths are expected in 2020 in
9、 the United Statesalone 1.To address this significant clinical problem,we have madeextensive efforts on several fronts,including the basic biology of cancer.Over the past several years,we have witnessed significant progress inour understanding of cancer genetics and relevant signaling pathwaysaffect
10、ing tumor phenotypes.We have also learned that tumors are notjust a mass of transformed cells but are comprised of other non-ma-lignant cells as well,ranging from fibroblasts,endothelial cells,andimmune cells to even microbes 28.As tumor cells progress to be-come highly malignant,their microenvironm
11、ent also co-evolves.In-deed,tumor cells continue to corrupt the non-malignant stromal cells asthey grow and use them to support their growth,metastasis,therapyresistance,and to evade the immune defense 915.Tumor-stromalinteractions are driven by growth factors,cytokines,metabolites,andother biomolec
12、ules secreted by the cells within the tumor micro-environment(TME).These interactions are often bidirectional and es-sential for optimal tumor growth,and thus provide targeting opportu-nities for effective clinical management.Natural products are generated in abundance by plants and marineorganisms
13、and have been utilized for centuries in traditional medicines16,17.Most of the bioactive natural products are secondary meta-bolites that aid in survival by often serving as mediators of innate de-fense mechanisms 18.These compounds gained significant attentionafter different epidemiological studies
14、 reported the health benefits ofthe consumption of certain fruits,vegetables,and their derived pro-ducts 1922.It also renewed the interest in ancient literature fromhttps:/doi.org/10.1016/j.semcancer.2020.05.009Received 8 October 2019;Received in revised form 10 May 2020;Accepted 14 May 2020Correspo
15、nding author at:Department of Pathology,College of Medicine;Cancer Biology Program,Mitchell Cancer Institute;University of South Alabama,1660Springhill Avenue,Mobile,AL 36604,USA.E-mail address:asinghsouthalabama.edu(A.P.Singh).1Present Address:Department of Computational Biology,St.Jude Childrens R
16、esearch Hospital,Memphis,TN,USA.2These authors contributed equally.Seminars in Cancer Biology xxx(xxxx)xxxxxx1044-579X/2020 Elsevier Ltd.All rights reserved.Please cite this article as:Haseeb Zubair,et al.,Seminars in Cancer Biology,https:/doi.org/10.1016/j.semcancer.2020.05.009Middle Eastern and So
17、uth Asian countries that reports healing powersof natural compounds and associated practices.Over the years,bioac-tive constituents from natural sources have been isolated and experi-mentallyvalidatedfortheiranti-viral,anti-bacterial,anti-in-flammatory,anti-fungal,andanti-cancerproperties21,2325.Ind
18、eed,about forty-seven percent of all anti-cancer drugs in clinical useare derived from the naturally-occurring compounds 26.These nat-ural compounds exhibit significant diversity in structure,function,andbiosynthesis,and therefore it is hard to classify them under strict ca-tegories.However,they are
19、 broadly put under four structural classesthat include terpenoids and steroids,alkaloids,fatty acid derivativesand polyketides,and phenylpropanoids 27.While the majority of theearlier studies investigated the effect of natural compounds on thetumor cells 28,29,the focus later expanded to include TME
20、 compo-nents as well.These efforts resulted in the demonstration of TME-modulating effects of natural agents in multiple cancer types,as re-viewed previously 3035.Recent years have witnessed significantlyincreased efforts towards understanding the roles of TME in cancerpathogenesis after the reporte
21、d success of immunotherapy in somecancer types 3638.Driven with this impetus,more and more naturalcompounds are now being evaluated for their TME-modulating prop-erties in parallel investigations 3941.In light of the new dataemerging from these efforts,it has become imperative that we revisitnatural
22、 compounds to understand their broader significance in themodulation of TME as well as associated mechanisms.This reviewprovides a comprehensive summary of the current literature on TME,especially highlighting its fundamental cellular and acellular compo-nents,and discusses their functions as well a
23、s the factors regulating thebehavior and functional properties of the stromal cells.After that,wediscuss the natural products of plant and marine origin that target TMEvia different mechanisms to confer their anti-cancer activity.The ex-pectation is that the presented discussion would encourage canc
24、erbiologists and cancer chemoprevention and therapy experts to engagein cross-disciplinary collaborations to allow future translational ad-vancements.2.The cellular component of the tumor microenvironmentPrincipal non-malignant cells within the TME are fibroblasts,en-dothelial cells,and immune cells
25、 such as macrophages,myeloid-derivedsuppressor cells(MDSCs),and lymphocytes.It has also recently beenrecognized that microbial cells are present within the TME and play anactive role in pathobiology and therapy-resistance(Fig.1).Below wediscuss in more detail about these cells,their functions,and th
26、eircharacteristics.2.1.Cancer-associated fibroblastsFibroblasts are the quiescent mesenchymal cells that are presentwithin the extracellular matrix(ECM)and play important roles in tissuerepair.Upon injury,these cells are activated and differentiate intomyofibroblasts through paracrine signaling 42,4
27、3.Their excessiveproliferation can result in organ fibrosis and may have unwanted con-sequences 44,45.Within the context of the tumor,these myofibro-blasts are referred to as cancer-associated fibroblasts(CAFs)3,6.Insome cases,CAFs can also be derived from other precursor cells,such asendothelial ce
28、lls,smooth muscle cells,and myoepithelial cells 2,46.Differentiation into the CAF phenotype is facilitated by factors derivedfrom tumor cells or other cells within the TME,such as IL-6,trans-forming growth factor-(TGF-),sonic hedgehog(SHH),and platelet-derived growth factor(PDGF)12,47,48.Microenviro
29、nmental stress(extracellular pH,hypoxia,radiation,and chemotherapy)can furtheraggravate this process likely to protect and support the tumor cells4951.Recently,the role of tumor-derived exosomes in CAFs gen-eration has also been reported 52.Morphologically,CAFs have a large spindle shape and express
30、 acytoskeletal protein,-smooth muscle actin(-SMA).Some othermarkers,such as fibroblast activation protein(FAP),platelet-derivedgrowth factor receptor-,and S100 calcium-binding protein A4,arealso used to identify CAFs 53,54.None of these markers are expressedexclusively by the CAFs because of their h
31、eterogeneous nature withintumortissues54,55.CAFsabundantlyproducecollagens,fi-bronectins,and hyaluronan,and these proteins,along with other ECMcomponents,form a highly dense fibrotic covering around the cancercells 55,56.Studies have suggested that CAFs can regulate tumorprogression and therapy resi
32、stance by inducing EMT,metabolic repro-gramming,activation of survival pathways,modulating anti-oxidantsystem,or stemness in tumor cells 38,55,57.CAFs also help in therecruitment of monocytes to the TME and promote their differentiationinto immunosuppressive MDSCs 58.2.2.Tumor-associated endothelial
33、 cellsTo meet their high demand for oxygen and nutrients,actively di-viding cancer cells recruit and activate the endothelial cells into theTME to facilitate the formation of new blood vessels from pre-existingblood capillaries 4.Endothelial cells form the inner lining of the bloodand lymphatic vess
34、els 59,60.Single-cell RNA sequencing data hassuggested that tumor-associated endothelial cells(TECs)are distinctfrom the normal ECs 61.Normal ECs form uniform monolayer withfew cytoplasmic projections,whereas TECs are irregular in shape andsize with long fragile,or thin cytoplasmic projections exten
35、ding acrossthe vessel lumen 4.TECs are CD31+and CD105+and appear in amosaic pattern within the tumor tissues 62.TME-derived cytokinesand growth factors such as interleukin-8(IL-8),vascular endothelialgrowth factor A(VEGF-A),and basic fibroblast growth factor(bFGF)aberrantly activate the TECs,which m
36、akes resultant blood vessels fra-gile,leaky and of irregular shape 59,63.Tumor cell-derived VEGF-A,IL-10,and prostaglandin E2 also induce Fas ligand(FasL)expression inTECs,which causes FasL-mediated apoptosis of CD8+T cells.However,regulatory T cells(Tregs)are not affected much since they express ah
37、igh level of anti-apoptotic protein,cellular FADD-like IL-1-convertingenzyme(FLICE)-inhibitory protein 64.2.3.Tumor-associated macrophagesMacrophages are part of the innate immune system and play activeand diverse roles due to their highly flexible nature.Based on the en-vironmental stimuli,they can
38、 differentiate either into M1(classical-activated macrophages,anti-tumor)or M2(alternative-activated mac-rophages,pro-tumor)phenotypes;a process often referred as macro-phage polarization 65,66.Innate or adaptive immune cell-derivedinterferon-(IFN-)or bacterial cell-derived lipopolysaccharide(LPS)in
39、duces M1 polarization,while Th2-type cytokines(IL-4,IL-10,and IL-13)polarize macrophages into M2 phenotype 67.In the context ofcancer,M2 macrophages are often referred to as tumor-associatedmacrophages(TAMs),and they are the significant component of tumor-infiltrating immune cells within the TME 67,
40、68.Unlike M1 macro-phages that rely mostly on glycolytic metabolism and produce pro-in-flammatory signals 69,70,M2 macrophages display oxidative phos-phorylationandsecreteanti-inflammatorycytokines71,72.Moreover,it is possible to convert M2 macrophages into the M1 subtypeby altering mitochondrial re
41、spiration 70,72.Both M1 and M2 mac-rophages express different markers.M1 subtype expresses induciblenitric oxide synthase(iNOS),suppressor of cytokine signaling 3(SOCS3),CD68,CD80,CD86,IL-1,IL-16,IL-12,IL-23,TNF-,IFN-,and CXCL-10 whereas M2 macrophages express arginase 1(Arg-1),CD163,CD200R,IL-10 an
42、d TGF-73.2.4.LymphocytesLymphocytes are white blood cells that include T cells,B cells,andH.Zubair,et al.Seminars in Cancer Biology xxx(xxxx)xxxxxx2natural killer(NK)cells.T-and B-cells are the part of adaptive immuneresponses,whereas NK cells are part of the innate arm of the immunesystem 74,75.T l
43、ymphocytes play a critical role in cancer immunityand are divided into four subtypes,CD4+T helper cell,CD8+cytotoxicT cell,memory T cells,and natural killer T cells(NKT)7678.CD4+Tcells help in B cell maturation and can also activate macrophages andcytotoxic T cells 79.They become functionally active
44、 after re-cognizing the antigen presented by major histocompatibility complex(MHC)class II molecules 79,80.On the other hand,CD8+T cellsrespond through MHC class I molecules and involve in the killing ofinfected or malignant tumor cells 80,81.Tumor cells and TME factorsdesensitize tumor-infiltrating
45、 lymphocytes(TILs),and they,in turn,build a tumor supportive immune microenvironment 5,82.The directanti-tumor activity of CD4+T cells is less explored because a majorityof the solid tumor cells do not express MHCII 79,80.However,thesecells confer anti-tumor activity indirectly either by secreting t
46、ype Icytokines or activating cytotoxic CD8+T cells 79,83.More im-portantly,a subset of tumor-supportive CD4+T cells,Tregs are foundwithin the TME.The normal biological function of Treg cells is to dis-tinguish between self and non-self-antigens that helps in the preventionof autoimmunity.Treg cells
47、express the IL-2 receptor(CD25)andForkhead Box P3(FoxP3)transcription factor,which is a master reg-ulator of Tregs functions 84.Treg cells cause immune suppression inseveralways.Notableamongtheseare;i)secretionofim-munosuppressive cytokines,IL-10,TGF-and IL-35;ii)consumption ofIL-2 from cellular mil
48、ieu;and iii)cytotoxic T lymphocyte-associatedprotein-4(CTLA-4)-mediated suppression of antigen-presenting cells orby induction of T cell exhaustion 84.Recently,it was demonstratedthat Treg cells indirectly induce the M2 population of macrophages inTME by inhibiting IFN-secretion 85.B cells infiltrat
49、ed into the TMEinduce memory CD4+T cell formation,promote proliferation andsurvival of activated CD8+T cells,and can also directly induce apop-tosis in tumor cells by secreting granzyme B 86.Indeed,a high densityof tumor-infiltrating B cell subtypes correlates with increased survival87.NK cells are
50、innate immune cells,express CD56,and are involvedin boosting the host immune defense against pathogens 88.Overall,these cells mediate anti-tumor and anti-viral immune response by ex-ecuting cytotoxic action through perforin and granzyme 89.2.5.Myeloid-derived suppressor cellsMyeloid cells are derive
