Abstract
An elaborate array of heterogeneous populations consisting of neoplastic cells, as well as recruited mesenchymal and inflammatory cells, form the tumor-associated stroma, a pathological milieu collectively known as the tumor microenvironment (TME). Although the traditional approach portrays carcinogenesis as the sum of genetic and epigenetic alterations that tumor cells undergo during the course of the multistep pathological process, over the last two decades, the TME has also been discovered to play an equally important role in determining tumor behavior. Broadly, the paracrine interactions that take place between tumor cells and the TME were found to influence the overall homeostasis, facilitating cancer growth and progression. The neoplastic evolution often benefits from the selective conditions of the TME, among them the presence of cancer-associated fibroblasts (CAFs), abnormal extracellular matrix (ECM) deposition, chronic inflammation, expanded vascularization, and immune response repression. This chapter will point out the main cellular and acellular components of the TME, focusing particular attention on how these tumor-derived factors and the underlying pathophysiological processes mentioned above play a role in innately modulating all aspects of cancer progression, starting with primary tumor growth and reaching the metastatic phase.
References
Abbasi MM, Mehdipour M, Monfaredan A et al (2015) Down-regulates erb/b2 oncogene expression and improves outcome of oral carcinoma in a rat model. Asian Pac J Cancer Prev 16:6947–6951
Abulaiti A, Shintani Y, Funaki S et al (2013) Interaction between non-small-cell lung cancer cells and fibroblasts via enhancement of TGF-𝛽 signaling by IL-6. Lung Cancer 82:204–213
Anderson NM, Simon MC (2020) The tumor microenvironment. Curr Biol 30:R921–R925
Baghban R, Roshangar L, Jahanban-Esfahlan R et al (2020) Tumor microenvironment complexity and therapeutic implications at a glance. Cell Commun Signal 18(1):59
Balahura LR, Selaru A, Dinescu S et al (2020) Inflammation and inflammasomes – pros and cons in tumorigenesis. J Immunol Res 2020:2549763
Balahura LR, Dinescu S, Balas M et al (2021) Cellulose nanofiber-based hydrogels embedding 5-FU promote pyroptosis activation in breast cancer cells and support human adipose-derived stem cell proliferation, opening new perspectives for breast tissue engineering. Pharmaceutics 13:1189
Bald T, Quast T, Landsberg J et al (2014) Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature 507:109–113
Balkwill F, Coussens LM (2004) Cancer: an inflammatory link. Nature 431:405–406
Balkwill F, Charles KA, Mantovani A (2005) Smoldering and polarised inflammation in the initiation and promotion of malignant disease. Cancer Cell 7:211–217
Balkwill FR, Capasso M, Hagemann T (2012) The tumor microenvironment at a glance. J Cell Sci 125:5591–5596
Bao B, Thakur A, Li Y et al (2012) The immunological contribution of NF-κB within the tumor microenvironment: a potential protective role of zinc as an anti-tumor agent. Biochim Biophys Acta Rev Cancer 1825:160–172
Beacham DA, Cukierman E (2005) Stromagenesis: the changing face of fibroblastic microenvironments during tumor progression. Semin Cancer Biol 15:329–341
Bent R, Moll L, Grabbe S et al (2018) Interleukin-1 beta – a friend or foe in malignancies? Int J Mol Sci 19:2155
Billings PC, Pacifici M (2015) Interactions of signaling proteins, growth factors and other proteins with heparan sulfate: mechanisms and mysteries. Connect Tissue Res 56:272–280
Binnewies M, Roberts EW, Kersten K et al (2018) Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med 24:541–550
Birbrair A (2018) Pericyte biology: development, homeostasis, and disease. Adv Exp Med Biol 1109:1–3
Boreddy SR, Sahu RP, Srivastava SK (2011) Benzyl isothiocyanate suppresses pancreatic tumor angiogenesis and invasion by inhibiting HIF-𝛼/VEGF/Rho-GTPases: pivotal role of STAT-3. PLoS One 6(10):e25799
Bos PD, Plitas G, Rudra D et al (2013) Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy. J Exp Med 210:2435–2466
Botta C, Misso G, Martino E et al (2016) The route to solve the interplay between inflammation, angiogenesis and anti-cancer immune response. Cell Death Dis 7:e2299
Casazza A, Laoui D, Wenes M et al (2013) Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores anti-tumor immunity. Cancer Cell 24:695–709
Chang CH, Qiu J, O’Sullivan D et al (2015) Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162:1229–1241
Chavdarov Chonov D, Krasimirova Ignatova MM, Ananiev JR et al (2019) IL-6 activities in the tumour microenvironment. Maced J Med Sci 7:2391–2398
Chen Y, Song Y, Du W et al (2019) Tumor-associated macrophages: an accomplice in solid tumor progression. J Biomed Sci 26:78
Chinai JM, Janakiram M, Chen F et al (2015) New immunotherapies targeting the PD-1 pathway. Trends Pharmacol Sci 36:587–595
Clambey ET, McNamee EN, Westrich JA et al (2012) Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci U S A 109:E2784–E2793
Coffelt SB, Kersten K, Doornebal C et al (2015) IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis. Nature 522:345–348
Colegio OR, Chu NQ, Szabo A et al (2014) Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513:559–563
Cooke VG, LeBleu VS, Keskin D et al (2012) Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cancer Cell 21:66–81
Corzo CA, Condamine T, Lu L et al (2010) HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med 207:2439–2453
Cox TR, Rumney R, Schoof E et al (2015) The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. Nature 522:106–110
Dang EV, Barbi J, Yang HY et al (2011) Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 146:772–784
David H (1988) Rudolf Virchow and modern aspects of tumor pathology. Pathol Res Pract 183:356–364
De Wever O, Mareel M (2003) Role of tissue stroma in cancer cell invasion. J Pathol 200:429–447
Demircioglu F, Wang J, Candid J et al (2020) Cancer associated fibroblast FAK regulates malignant cell metabolism. Nat Commun 11(1):1290
DeNardo DG, Barreto JB, Andreu P et al (2009) CD4+ T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16:91–102
Dhani N, Fyles A, Hedley D et al (2015) The clinical significance of hypoxia in human cancers. Semin Nucl Med 45:110–121
Doedens AL, Stockmann C, Rubinstein MP et al (2010) Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression. Cancer Res 70:7465–7475
Doedens AL, Phan A, Stradner M et al (2013) Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen. Nat Immunol 14:1173–1182
Dunn GP, Old LJ, Schreiber RD (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21:137–148
DuPage M, Cheung AF, Mazumdar C et al (2011) Endogenous T cell responses to antigens expressed in lung adenocarcinomas delay malignant tumor progression. Cancer Cell 19:72–85
Eyles J, Puaux AL, Wang X et al (2010) Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma. J Clin Investig 120:2030–2039
Facciabene A, Peng X, Hagemann IS et al (2011) Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 475:226–230
Filatova A, Seidel S, Bogurcu N et al (2016) Acidosis acts through HSP90 in a PHD/VHL-Independent manner to promote HIF function and stem cell maintenance in glioma. Cancer Res 76:5845–5856
Finisguerra V, Di Conza G, Di Matteo M et al (2015) MET is required for the recruitment of anti-tumoural neutrophils. Nature 522:349–353
Flannagan RS, Cosío G, Grinstein S (2009) Antimicrobial mechanisms of phagocytes and bacterial evasion strategies. Nat Rev Microbiol 7(5):355–366
Franklin RA, Liao W, Sarkar A et al (2014) The cellular and molecular origin of tumor-associated macrophages. Science 344:921–925
Fridman WH, Pages F, Sautes-Fridman C et al (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12:298–306
Gabrilovich DI, Ostrand-Rosenberg S, Bronte V (2012) Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12:253–268
Gelfo V, Romaniello D, Mazzeschi M et al (2020) Roles of IL-1 in cancer: from tumor progression to resistance to targeted therapies. Int J Mol Sci 21:6009
Giatromanolaki A, Sivridis E, Koukourakis MI (2007) The pathology of tumor stromatogenesis. Cancer Biol Ther 6:639–645
Gok YB, Gunaydin G, Gedik ME et al (2019) Cancer associated fibroblasts sculpt tumour microenvironment by recruiting monocytes and inducing immunosuppressive PD-1+ TAMs. Sci Rep 9:3172
Goubran HA, Kotb RR, Stakiw J et al (2014) Regulation of tumor growth and metastasis: the role of tumor microenvironment. Cancer Growth Metastasis 7:9–18
Granot Z, Henke E, Comen EA et al (2011) Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell 20:300–314
Hanna RN, Cekic C, Sag D et al (2015) Patrolling monocytes control tumor metastasis to the lung. Science 350:985–990
Hannani D, Ma Y, Yamazak T et al (2012) Harnessing γδ T cells in anticancer immunotherapy. Trends Immunol 33:199–206
Headley MB, Bins A, Nip A et al (2016) Visualization of immediate immune responses to pioneer metastatic cells in the lung. Nature 531:513–517
Helfen A, Roth J, Ng T et al (2018) In vivo imaging of pro- and antitumoral cellular components of the tumor microenvironment. J Nucl Med 59:183–188
Imtiyaz HZ, Williams EP, Hickey MM et al (2010) Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation. J Clin Invest 120:2699–2714
Jiang X, Wang J, Deng X et al (2020) The role of microenvironment in tumor angiogenesis. J Exp Clin Cancer Res 39(1):204
Jin J, Lin J, Xu A et al (2021) CCL2: an important mediator between tumor cells and host cells in tumor microenvironment. Front Oncol 11:722916
Joyce JA, Pollard JW (2009) Microenvironmental regulation of metastasis. Nat Rev Cancer 9:239–252
Kitamura T, Qian BZ, Pollard JW (2015a) Immune cell promotion of metastasis. Nat Rev Immunol 15:73–86
Kitamura T, Qian BZ, Soong D et al (2015b) CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J Exp Med 212:1043–1059
Koh MY, Lemos R Jr, Liu X et al (2011) The hypoxia-associated factor switches cells from HIF-1alpha- to HIF-2alpha-dependent signaling promoting stem cell characteristics, aggressive tumor growth and invasion. Cancer Res 71:4015–4027
Kong L, Zhou Y, Bu H et al (2016) Deletion of interleukin-6 in monocytes/macrophages suppresses the initiation of hepatocellular carcinoma in mice. J Exp Clin Cancer Res 35:131
Koukourakis MI, Giatromanolaki A, Harris AL et al (2006) Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: a metabolic survival role for tumor-associated stroma. Cancer Res 66:632–637
Kumar V, Donthireddy L, Marvel D et al (2017) Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors. Cancer Cell 32:654–668
Landskron G, De la Fuente M, Thuwaji P et al (2014) Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res 2014:149–185
Laoui D, Van Overmeire E, Di Conza G et al (2014) Tumor hypoxia does not drive differentiation of tumor-associated macrophages but rather fine-tunes the M2-like macrophage population. Cancer Res 74:24–30
Laviron M, Boissonnas A (2019) Ontogeny of tumor-associated macrophages. Front Immunol 10:1799
Lazar AD, Dinescu S, Costache M (2020) Deciphering the molecular landscape of cutaneous squamous cell carcinoma for better diagnosis and treatment. J Clin Med 9:2228
Lazăr AD, Dinescu S, Costache M (2020) The non-coding landscape of cutaneous malignant melanoma: a possible route to efficient targeted therapy. Cancers 12:3378
Lee HJ, Ryu J, Jung Y et al (2016) Glycerol-3-phosphate acyltransferase-1 upregulation by O-GlcNAcylation of Sp1 protects against hypoxia-induced mouse embryonic stem cell apoptosis via mTOR activation. Cell Death Dis 7:e2158
Lees JR (2015) Interferon-γ in autoimmunity: a complicated player on a complex stage. Cytokine 74:18–26
Li Q, Fu GB, Zheng JT et al (2013) NADPH oxidase subunit p22(phox)-mediated reactive oxygen species contribute to angiogenesis and tumor growth through AKT and ERK1/2 signaling pathways in prostate cancer. BBA 12:3375–3385
Li A, Vincent J, Cates DM et al (2009) Low levels of tumor necrosis factor 𝛼 increase tumor growth by inducing an endothelial phenotype of monocytes recruited to the tumor site. Cancer Res 69:338–348
Li R, Hebert JD, Lee TA et al (2017) Macrophage-secreted TNFα and TGFβ1 influence migration speed and persistence of cancer cells in 3D tissue culture via independent pathways. Cancer Res 77:279–320
Liao D, Johnson RS (2007) Hypoxia: a key regulator of angiogenesis in cancer. Cancer Metastasis Rev 26:281–290
Lin Y, Choksi S, Shen HM et al (2004) Tumor necrosis factor-induced nonapoptotic cell death requires receptor-interacting protein-mediated cellular reactive oxygen species accumulation. J Biol Chem 279:10822–10828
Lin Y, Xu J, Lan H (2019) Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications. J Hematol Oncol 12:76
Liu G, Bi Y, Shen B et al (2014) SIRT1 limits the function and fate of myeloid-derived suppressor cells in tumors by orchestrating HIF-1alpha-dependent glycolysis. Cancer Res 74:727–737
Lu X, Kang Y (2010) Hypoxia and hypoxia-inducible factors: master regulators of metastasis. Clin Cancer Res 16:5928–5935
Mantovani A, Barajon I, Garlanda C (2018) IL-1 and IL-1 regulatory pathways in cancer progression and therapy. Immunol Rev 281:57–61
McAllister SS, Weinberg RA (2014) The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat Cell Biol 16:717–727
Mojic M, Takeda K, Hayakawa Y (2017) The dark side of IFN-γ: its role in promoting cancer immunoevasion. Int J Mol Sci 19:89
Montfort A, Colacios C, Levade T et al (2019) The TNF Paradox in cancer progression and immunotherapy. Front Immunol 10:1818
Morrison D, Parvani JG, Schiemann WP (2013) The relevance of the TGF-𝛽 paradox to EMT-MET programs. Cancer Lett 341:30–40
Murata M, Thanan R, Ma N et al (2012) Role of nitrative and oxidative DNA damage in inflammation-related carcinogenesis. Biomed Biotechnol 2012:623019
Natarajan S, Foreman KM, Soriano MI et al (2019) Collagen remodeling in the hypoxic tumor-mesothelial niche promotes ovarian cancer metastasis. Cancer Res 79(9):2271–2284
Neophytou CM, Pierides C, Christodoulou MI et al (2020) The role of tumor-associated myeloid cells in modulating cancer therapy. Front Oncol 10:899
Neophytou CM, Panagi M, Stylianopoulos T et al (2021) The role of tumor microenvironment in cancer metastasis: molecular mechanisms and therapeutic opportunities. Cancers 13:2053
Noman MZ, Desantis G, Janji B et al (2014) PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med 211:781–790
Nurmik M, Ullmann P, Rodriguez F et al (2020) In search of definitions: cancer-associated fibroblasts and their markers. Int J Cancer 146:895–905
Nyberg P, Salo T, Kalluri R (2008) Tumor microenvironment and angiogenesis. Front Biosci 13:6537
Nywening TM, Wang-Gillam A, Sanford DE et al (2016) Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a singlecentre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol 17:651–662
Ohta A, Gorelik E, Prasad SJ et al (2006) A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci U S A 103:13132–13137
Otrock ZK, Hatoum HA, Awada AH et al (2009) Hypoxiainducible factor in cancer angiogenesis: structure, regulation and clinical perspectives. Crit Rev Oncol Hematol 70:93–102
Ottensmeier CH, Perry KL, Harden EL et al (2016) Upregulated glucose metabolism correlates inversely with CD8+T-cell infiltration and survival in squamous cell carcinoma. Cancer Res 76:4136–4148
Paolino M, Choidas A, Wallner S et al (2014) The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nat Cell Biol 507:508–512
Papageorgis P (2015) TGFbeta signaling in tumor initiation, epithelial-to-mesenchymal transition, and metastasis. J Oncol 2015:587193
Pastula A, Marcinkiewicz J (2011) Myeloid-derived suppressor cells: a double-edged sword? Int J Exp Pathol 92:73–78
Pauken KE, Wherry EJ (2015) Overcoming T cell exhaustion in infection and cancer. Trends Immunol 36:265–276
Pauken KE, Sammons MA, Odorizzi PM et al (2016) Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354:1160–1165
Petrova V, Annicchiarico-Petruzzelli M, Melino G et al (2018) The hypoxic tumour microenvironment. Oncogenesis 7(1):10
Philip M, Fairchild L, Sun L et al (2017) Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature 545:452–456
Pietras K, Ostman A (2010) Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res 316:1324–1331
Qian B, Deng Y, Im JH et al (2009) Distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS One 4:e6562
Qian BZ, Li J, Zhang H et al (2011) CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475:222–225
Qian S, Golubnitschaja O, Zhan X (2019) Chronic inflammation: key player and biomarker-set to predict and prevent cancer development and progression based on individualized patient profiles. EPMA J 10(4):365–381
Robinson BD, Sica GL, Liu YF et al (2009) Tumor microenvironment of metastasis in human breast carcinoma: a potential prognostic marker linked to hematogenous dissemination. Clin Cancer Res 15:2433–2441
Romero-Garcia S, Lopez-Gonzalez JS, Báez-Viveros JL et al (2011) Tumor cell metabolism: an integral view. Cancer Biol Ther 12:939–948
Ruffell B, Chang-Strachan D, Chan V et al (2014) Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell 26:623–637
Samatov TR, Tonevitsky AG, Schumacher U (2013) Epithelial-mesenchymal transition: focus on metastatic cascade, alternative splicing, non-coding RNAs and modulating compounds. Mol Cancer 12(1):107
Sanchez LR, Borriello L, Entenberg D et al (2019) The emerging roles of macrophages in cancer metastasis and response to chemotherapy. J Leukoc Biol 106:259–274
Santibanez JF, Quintanilla M, Bernabeu C (2011) TGF-𝛽/TGF-𝛽 receptor system and its role in physiological and pathological conditions. Clin Sci 121:233–251
Saraiva M, Vieira P, O’Garra A (2020) Biology and therapeutic potential of interleukin-10. J Exp Med 217(1):e20190418
Schietinger A, Philip M, Krisnawan VE et al (2016) Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis. Immunity 45(2):389–401
Schito L, Semenza GL (2016) Hypoxia-inducible factors: master regulators of cancer progression. Trends Cancer 2:758–770
Semba H, Takeda N, Isagawa T et al (2016) HIF-1α-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity. Nat Commun 7:11635
Shen M, Kang Y (2018) Complex interplay between tumor microenvironment and cancer therapy. Front Med 12(4):426–439
Sivridis E, Giatromanolaki A, Koukourakis MI (2004) Stromatogenesis and tumour progression. Int J Surg Pathol 12:1–9
Smith HA, Kang Y (2013) The metastasis-promoting roles of tumor-associated immune cells. J Mol Med 91:411–429
Srinivasan S, Chitalia V, Meyer RD et al (2015) Hypoxia-induced expression of phosducin-like 3 regulates expression of VEGFR-2 and promotes angiogenesis. Angiogenesis 18(4):449–462
Stylianopoulos T, Martin JD, Snuderl M et al (2013) Coevolution of solid stress and interstitial fluid pressure in tumors during progression: implications for vascular collapse. Cancer Res 73:3833–3841
Sun S, Dong H, Yan T et al (2020) Role of TSP-1 as prognostic marker in various cancers: a systematic review and meta-analysis. BMC Med Genet 21(1):139
Szostak B, Machaj F, Rosik J et al (2019) CTLA4 antagonists in phase I and phase II clinical trials, current status and future perspectives for cancer therapy. Expert Opin Investig Drugs 28(2):149–159
Topalian SL, Taube JM, Anders RA et al (2016) Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 16:275–287
Triner D, Shah YM (2016) Hypoxia-inducible factors: a central link between inflammation and cancer. J Clin Invest 126:3689–3698
Tsai YP, Wu KJ (2012) Hypoxia-regulated target genes implicated in tumor metastasis. J Biomed Sci 19:102
van Grevenstein WM, Hofland LJ, van Rossen ME et al (2007) Inflammatory cytokines stimulate the adhesion of colon carcinoma cells to mesothelial monolayers. Dig Dis Sci 52(10):2775–2783
Wang R, Zhang J, Chen S et al (2011) Tumor-associated macrophages provide a suitable microenvironment for non-small lung cancer invasion and progression. Lung Cancer 74:188–196
Wang M, Zhao J, Zhang L et al (2017) Role of tumor microenvironment in tumorigenesis. J Cancer 8:761–773
Wculek SK, Malanchi I (2015) Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature 528:413–417
Wei R, Liu S, Zhang S et al (2020) Cellular and extracellular components in tumor microenvironment and their application in early diagnosis of cancers. Anal Cell Pathol (Amst) 2020:6283796
Wherry EJ (2011) T cell exhaustion. Nat Immunol 12:492–499
Willimsky G, Blankenstein T (2005) Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature 437:141–146
Xu J, Lamouille S, Derynck R (2009) TGF-Β-induced epithelial to mesenchymal transition. Cell Res 19:156–172
Yan Y, Chen X, Wang X et al (2019) The effects and the mechanisms of autophagy on the cancer-associated fibroblasts in cancer. J Exp Clin Cancer Res 38:171
Yang S, Gao H (2017) Nanoparticles for modulating tumor microenvironment to improve drug delivery and tumor therapy. Pharmacol Res 126:97–108
Yang H, Bocchetta M, Kroczynska B et al (2006) TNF-alpha inhibits asbestos-induced cytotoxicity via a NF-kappaB-dependent pathway, a possible mechanism for asbestos-induced oncogenesis. Proc Natl Acad Sci U S A 103(27):10397–10402
Yang J, Yan J, Liu B (2018) Targeting VEGF/VEGFR to modulate antitumor immunity. Front Immunol 9:978
Zhao X, Sun G, Sun X et al (2016) A novel differentiation pathway from CD4+ T cells to CD4− T cells for maintaining immune system homeostasis. Cell Death Dis 7(4):e2193
Zhu Y, Herndon JM, Sojka DK et al (2017) Tissue-resident macrophages in pancreatic ductal adenocarcinoma originate from embryonic hematopoiesis and promote tumor progression. Immunity 47(3):597
Acknowledgments
This work was supported by UEFISCDI PN-III-P1-1.1-PD-2016-2057 (46PD/2018).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2022 Springer Nature Switzerland AG
About this entry
Cite this entry
Balahura (Stamat), LR., Lazar, AD., Dinescu, S., Costache, M. (2022). Tumor Microenvironment Complexity: A Pathological Milieu that Innately Modulates Cancer Progression. In: Rezaei, N. (eds) Handbook of Cancer and Immunology. Springer, Cham. https://doi.org/10.1007/978-3-030-80962-1_89-1
Download citation
DOI: https://doi.org/10.1007/978-3-030-80962-1_89-1
Received:
Accepted:
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-80962-1
Online ISBN: 978-3-030-80962-1
eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences