Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5563_Библиотеки_им_академика_М_И_Перельмана.pdf
76 The Dynamics of Tumor Microenvironment and Therapeutic Targets
221. Zhang D, Wang Y, Shi Z, Liu J, Sun P, Hou X, et al. Metabolic reprogramming of cancer-
associated broblasts by IDH3α downregulation. Cell Rep. 2015;10:1335–1348.
222. Shim H, Dolde C, Lewis BC, Wu C-S, Dang G, Jungmann RA, et al. c-Myc transacti-
vation of LDH-A: Implications for tumor metabolism and growth. Proc Natl Acad Sci.
1997;94:6658–6663.
223. Lee K-W, Yeo S-Y, Gong J-R, Koo O-J, Sohn I, Lee WY, et al. PRRX1 is a master
transcription factor of stromal broblasts for myobroblastic lineage progression. Nat
Commun
. 2022;13:2793.
224. Kogure A, Naito Y, Yamamoto Y, Yashiro M, Kiyono T, Yanagihara K, et al. Cancer
cells with high-metastatic potential promote a glycolytic shift in activated broblasts.
PLoS One
. 2020;15:e0234613.
225. Monteran L, Erez N. The dark side of broblasts: Cancer-associated broblasts as
mediators of immunosuppression in the tumor microenvironment. Front Immunol.
2019;10:1835.
226. Li Y, Zhao Z, Liu W, Li X. SNHG3 functions as miRNA sponge to promote breast
cancer cells growth through the metabolic reprogramming. Appl Biochem Biotechnol.
2020;19
1:1084–1099.
227. Li Z, Sun C, Qin Z. Metabolic reprogramming of cancer-associated broblasts and its
effect on cancer cell reprogramming. Theranostics. 2021;11:8322.
228. Kock A, Larsson K, Bergqvist F, Eissler N, Elfman LHM, Raouf J, et al. Inhibition
of microsomal prostaglandin E synthase-1 in cancer-associated broblasts suppresses
neurobl
astoma tumor growth. EBioMedicine. 2018;32:84–92.
229. Elwakeel E, Brüggemann M, Wagih J, Lityagina O, Elewa MAF, Han Y, et al. Disruption
of prostaglandin E2 signaling in cancer-associated broblasts limits mammary carci-
noma gro
wth but promotes metastasis. Cancer Res. 2022;82:1380–1395.
230. Wan X, Guan S, Hou Y, Qin Y, Zeng H, Yang L, et al. FOSL2 promotes VEGF-
independent angiogenesis by transcriptionnally activating Wnt5a in breast cancer-
associated broblasts. Theranostics. 2021;11:4975.
231. Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: Beyond discovery and
development. Cell. 2019;176:1248–1264.
232. De Francesco EM, Lappano R, Santolla MF, Marsico S, Caruso A, Maggiolini M.
HIF-1α/GPER signaling mediates the expression of VEGF induced by hypoxia in breast
cancer associated broblasts (CAFs). Breast Cancer Res. 2013;15:1–18.
233. Chen X, Song E. Turning foes to friends: Targeting cancer-associated broblasts. Nat
Rev Drug Discov. 2019;18:99–115.
234. De Palma M, Biziato D, Petrova TV. Microenvironmental regulation of tumour angio-
genesis. Nat Rev Cancer. 2017;17:457–474.
235. Tsai Y-M, Wu K-L, Liu Y-W, Chang W-A, Huang Y-C, Chang C-Y, et al. Cooperation
between cancer and broblasts in vascular mimicry and N2-type neutrophil recruit-
ment via N
otch2–Jagged1 interaction in lung cancer. Front Oncol. 2021;11:696931.
236. Shen Y-W, Zhou Y-D, Chen H-Z, Luan X, Zhang W-D. Targeting CTGF in cancer: An
emerging therapeutic opportunity. Trends in Cancer. 2021;7:511–524.
237. Ohara Y, Enomoto A, Tsuyuki Y, Sato K, Iida T, Kobayashi H, et al. Connective tissue
growth factor produced by cancer-associated broblasts correlates with poor prognosis
in epithelioid malignant pleural mesothelioma. Oncol Rep. 2020;44:838–848.
238. Watanabe K, Shiga K, Maeda A, Harata S, Yanagita T, Suzuki T, et al. Chitinase 3-like
1 secreted from cancer-associated broblasts promotes tumor angiogenesis via interleu-
kin-8 se
cretion in colorectal cancer. Int J Oncol. 2021;60:3.
239. Asangani IA, Rasheed SAK, Nikolova DA, Leupold JH, Colburn NH, Post S, et al.
MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4
77Cancer-Associated Fibroblasts and Glioblastoma
and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene.
2008;27:2128–2136.
240. Yang F, Ning Z, Ma L, Liu W, Shao C, Shu Y, et al. Exosomal miRNAs and miRNA
dysregulation in cancer-associated broblasts. Mol Cancer. 2017;16:1–10.
241. Pelon F, Bourachot B, Kieffer Y, Magagna I, Mermet-Meillon F, Bonnet I, et al. Cancer-
associated broblast heterogeneity in axillary lymph nodes drives metastases in breast
cancer th
rough complementary mechanisms. Nat Commun. 2020;11:404.
242. Daniel SK, Seo YD, Pillarisetty VG. The CXCL12-CXCR4/CXCR7 axis as a mech-
anism of immune resistance in gastrointestinal malignancies. Semin Cancer Biol.
2020;65:176–188, Elsevier.
243. Zhou S-L, Dai Z, Zhou Z-J, Chen Q, Wang Z, Xiao Y-S, et al. CXCL5 contributes
to tumor metastasis and recurrence of intrahepatic cholangiocarcinoma by recruiting
inltr
ative intratumoral neutrophils. Carcinogenesis. 2014;35:597–605.
244. Dumont N, Liu B, DeFilippis RA, Chang H, Rabban JT, Karnezis AN, et al. Breast
broblasts modulate early dissemination, tumorigenesis, and metastasis through altera-
tion of ext
racellular matrix characteristics. Neoplasia. 2013;15:249-IN7.
245. Xiao Q, Ge G. Lysyl oxidase, extracellular matrix remodeling and cancer metastasis.
Cancer Microenviron. 2012;5:261–273.
246. Zhang Y, Gu Z, Wan J, Lou X, Liu S, Wang Y, et al. Stearoyl-CoA desaturase-1 depen-
dent lipid droplets accumulation in cancer-associated broblasts facilitates the progres-
sion of lung cancer. Int J Biol Sci. 2022;18:6114.
247. Min K-W, Kim D-H, Noh Y-K, Son BK, Kwon MJ, Moon J-Y. Cancer-associated bro-
blasts are associated with poor prognosis in solid type of lung adenocarcinoma in a
machine learning analysis. Sci Rep. 2021;11:16779.
248. Paolillo M, Schinelli S. Extracellular matrix alterations in metastatic processes. Int J
Mol Sci. 2019;20:4947.
249. Nguyen EV, Pereira BA, Lawrence MG, Ma X, Rebello RJ, Chan H, et al. Proteomic pro-
ling of human prostate Cancer-associated broblasts (CAF) reveals LOXL2-dependent
regulation of the tumor microenvironment*[S]. Mol Cell Proteomics. 2019;18:1410–1427.
250. Yang X, Li Y, Zou L, Zhu Z. Role of exosomes in crosstalk between cancer-associated
broblasts and cancer cells. Front Oncol. 2019;9:356.
251. Li C, Teixeira AF, Zhu H-J, Ten Dijke P. Cancer associated-broblast-derived exosomes
in cancer progression. Mol Cancer. 2021;20:154.
252. Brechbuhl HM, Barrett AS, Kopin E, Hagen JC, Han AL, Gillen AE, et al. Fibroblast
subtypes dene a metastatic matrisome in breast cancer. JCI Insight. 2020;5.
253. Hassanpour M, Rezaie J, Darabi M, Hiradfar A, Rahbarghazi R, Nouri M. Autophagy
modulation altered differentiation capacity of CD146+ cells toward endothelial cells,
pericytes, and cardiomyocytes. Stem Cell Res Ther. 2020;11:1–14.
254. Manocha E, Consonni A, Baggi F, Ciusani E, Cocce V, Paino F, et al. CD146+ pericytes
subset isolated from human micro-fragmented fat tissue display a strong interaction
with endothelial cells: Apotential cell target for therapeutic angiogenesis. Int J Mol Sci.
2022;23:5806.
255. Hilmi M, Nicolle R, Bousquet C, Neuzillet C. Cancer-associated broblasts: Accom-
plices in the tumor immune evasion. Cancers (Basel). 2020;12:2969.
256. Linares J, Marín-Jiménez JA, Badia-Ramentol J, Calon A. Determinants and func-
tions of CAFs secretome during cancer progression and therapy. Front Cell Dev Biol.
2021;8:621070.
257. Wessolly M, Mairinger E, Borchert S, Bankfalvi A, Mach P, Schmid KW, et al. CAF-
associated paracrine signaling worsens outcome and potentially contributes to chemo-
resistance in epithelial ovarian cancer. Front Oncol. 2022;12:798680.
78 The Dynamics of Tumor Microenvironment and Therapeutic Targets
258. Peiris-Pagès M, Sotgia F, Lisanti MP. Chemotherapy induces the cancer-associated
broblast phenotype, activating paracrine Hedgehog-GLI signalling in breast cancer
cells. Oncotarget. 2015;6:10728.
259. Powell DR, Huttenlocher A. Neutrophils in the tumor microenvironment. Trends
Immunol. 2016;37:41–52.
260. Maji S, Panda S, Samal SK, Shriwas O, Rath R, Pellecchia M, et al. Bcl-2 antiapoptotic
family proteins and chemoresistance in cancer. Adv Cancer Res. 2018;137:37–75.
261. Cheteh EH, Sarne V, Ceder S, Bianchi J, Augsten M, Rundqvist H, et al. Interleukin-6
derived from cancer-associated broblasts attenuates the p53 response to doxorubicin
in prost
ate cancer cells. Cell Death Discov. 2020;6:42.
262. Gao Y, Li X, Zeng C, Liu C, Hao Q, Li W, et al. CD63+ cancer-associated broblasts
confer tamoxifen resistance to breast cancer cells through exosomal miR−22. Adv Sci.
2020;7:20
02518.
263. Fang Y, Zhou W, Rong Y, Kuang T, Xu X, Wu W, et al. Exosomal miRNA-106b from
cancer-associated broblast promotes gemcitabine resistance in pancreatic cancer. Exp
Cell Re
s. 2019;383:111543.
264. Erkan M, Hausmann S, Michalski CW, Fingerle AA, Dobritz M, Kleeff J, et al. The
role of stroma in pancreatic cancer: Diagnostic and therapeutic implications. Nat Rev
Gastroen
terol Hepatol. 2012;9:454–467.
265. Hosein AN, Brekken RA, Maitra A. Pancreatic cancer stroma: An update on therapeu-
tic targeting strategies. Nat Rev Gastroenterol Hepatol. 2020;17:487–505.
266. Liu Y, Xun Z, Ma K, Liang S, Li X, Zhou S, et al. Identication of a tumour immune
barrier in the HCC microenvironment that determines the efcacy of immunotherapy.
J Hepat
ol. 2023;78:770 –782.
267. Flavell RA, Sanjabi S, Wrzesinski SH, Licona-Limón P. The polarization of immune
cells in the tumour environment by TGFβ. Nat Rev Im
munol. 2010;10:554–567.
268. Teicher BA, Fricker SP. CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res.
2010;16:2927–2931.
269. Wu X, Qian L, Zhao H, Lei W, Liu Y, Xu X, et al. CXCL12/CXCR4: An amazing chal-
lenge and opportunity in the ght against brosis. Ageing Res Rev. 2023;83:101809.
270. Santagata S, Ieranò C, Trotta AM, Capiluongo A, Auletta F, Guardascione G, et al.
CXCR4 and CXCR7 signaling pathways: Afocus on the cross-talk between cancer cells
and tumor microenvironment. Front Oncol. 2021;11:591386.
271. Sun C, Mezzadra R, Schumacher TN. Regulation and function of the PD-L1 check-
point. Immunity. 2018;48:434–452.
272. Mhaidly R, Mechta-Grigoriou F. Role of cancer-associated broblast subpopula-
tions in immune inltration, as a new means of treatment in cancer. Immunol Rev.
2021;302:259–272.
273. Deng Y, Cheng J, Fu B, Liu W, Chen G, Zhang Q, et al. Hepatic carcinoma-associated
broblasts enhance immune suppression by facilitating the generation of myeloid-
derived suppressor cells. Oncogene. 2017;36:1090–1101.
274. Xiang X, Niu Y-R, Wang Z-H, Ye L-L, Peng W-B, Zhou Q. Cancer-associated bro-
blasts: Vital suppressors of the immune response in the tumor microenvironment.
Cytokine Growth Factor Rev. 2022;67:35–48.
275. Farhood B, Naja M, Mortezaee K. CD8+ cytotoxic T lymphocytes in cancer immuno-
therapy: Areview. J Cell Physiol. 2019;234:8509–8521.
276. Lakins MA, Ghorani E, Munir H, Martins CP, Shields JD. Cancer-associated bro-
blasts induce antigen-specic deletion of CD8+ T Cells to protect tumour cells. Nat
Commun. 2018;9:948.
277. Fujii N, Yashiro M, Hatano T, Fujikawa H, Motomura H. Cd9-positive exosomes
derived from cancer-associated broblasts might inhibit the proliferation of Malignant
melanoma cells. Anticancer Res. 2023;43:25–33.
79Cancer-Associated Fibroblasts and Glioblastoma
278. Remsing Rix LL, Sumi NJ, Hu Q, Desai B, Bryant AT, Li X, et al. IGF-binding proteins
secreted by cancer-associated broblasts induce context-dependent drug sensitization
of lung ca
ncer cells. Sci Signal. 2022;15:eabj5879.
279. Tanaka R, Kimura K, Eguchi S, Ohira G, Tanaka S, Amano R, et al. Interleukin-8 pro-
duced from cancer-associated broblasts suppresses proliferation of the OCUCh-LM1
cancer cell line. BMC Cancer. 2022;22:748.
280. Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. The 2021
WHO classication of tumors of the central nervous system: Asummary. Neuro Oncol.
2021;2
3:1231–1251.
281. Chang K, Zhang B, Guo X, Zong M, Rahman R, Sanchez D, et al. Multimodal imaging
patterns predict survival in recurrent glioblastoma patients treated with bevacizumab.
Neuro Onco
l. 2016;18:1680–1687.
282. Zou Y, Sun X, Yang Q, Zheng M, Shimoni O, Ruan W, et al. Blood-brain barrier–
penetrating single CRISPR-Cas9 nanocapsules for effective and safe glioblastoma gene
therapy. Sci Adv. 2022;8:eabm8011.
283. Pombo Antunes AR, Scheyltjens I, Duerinck J, Neyns B, Movahedi K, Van Ginderachter
JA. Understanding the glioblastoma immune microenvironment as basis for the devel-
opment of new immunotherapeutic strategies. Elife. 2020;9:e52176.
284. De Visser KE, Joyce JA. The evolving tumor microenvironment: From cancer initiation
to metastatic outgrowth. Cancer Cell. 2023;41:374–403.
285. Henke E, Nandigama R, Ergün S. Extracellular matrix in the tumor microenvironment
and its impact on cancer therapy. Front Mol Biosci. 2020;6:160.
286. Kalli M, Poskus MD, Stylianopoulos T, Zervantonakis IK. Beyond matrix stiffness:
Targeting force-induced cancer drug resistance. Trends in Cancer. 2023;9(11):937-954.
doi:10
.1016/j.trecan.2023.07.006.
287. Chen S, Morine Y, Tokuda K, Yamada S, Saito Y, Nishi M, et al. Cancer-associated
broblast-induced M2-polarized macrophages promote hepatocellular carcinoma
progression via the plasminogen activator inhibitor-1 pathway. Int J Oncol. 2021;
59:1–14.
288. Jung E, Osswald M, Ratliff M, Dogan H, Xie R, Weil S, et al. Tumor cell plastic-
ity, heterogeneity, and resistance in crucial microenvironmental niches in glioma. Nat
Commun. 2021;12:1014.
289. Jain S, Rick JW, Joshi RS, Beniwal A, Spatz J, Gill S, et al. Single-cell RNA sequencing
and spatial transcriptomics reveal cancer-associated broblasts in glioblastoma with
protumoral effects. J Clin Invest. 2023;133.
290. Zuo M, Zhang S, Chen S, Xiang Y, Yuan Y, Li T, et al. Glioma-associated broblasts
promote glioblastoma resistance to temozolomide through CCL2-CCR2 paracrine sig-
naling. BioRxiv. 2024:2003–2024.
291. Zhang C, Fei Y, Wang H, Hu S, Liu C, Hu R, et al. CAFs orchestrates tumor immune
microenvironment—a new target in cancer therapy? Front Pharmacol. 2023;14:1113378.
292. Friebel E, Kapolou K, Unger S, Núñez NG, Utz S, Rushing EJ, et al. Single-cell map-
ping of human brain cancer reveals tumor-specic instruction of tissue-invading leuko-
cytes. Cell. 2020;181:1626–1642.
293. Hambardzumyan D, Gutmann DH, Kettenmann H. The role of microglia and macro-
phages in glioma maintenance and progression. Nat Neurosci. 2016;19:20–27.
294. Gutmann DH, Kettenmann H. Microglia/brain macrophages as central drivers of brain
tumor pathobiology. Neuron. 2019;104:442–449.
295. Bonavita E, Bromley CP, Jonsson G, Pelly VS, Sahoo S, Walwyn-Brown K, et al.
Antagonistic inammatory phenotypes dictate tumor fate and response to immune
checkpoint blockade. Immunity. 2020;53:1215–1229.
296. Kim DJ, Dunleavey JM, Xiao L, Ollila DW, Troester MA, Otey CA, Li W, Barker
TH, Dudley AC. Suppression of TGFβ-mediated conversion of endothelial cells and
80 The Dynamics of Tumor Microenvironment and Therapeutic Targets
broblasts into cancer associated (myo) broblasts via HDAC inhibition. Br. J. Cancer.
2018 May 15;118(10):1359–1368.
297. Zhu Y, Zhang L, Zha H, Yang F, Hu C, Chen L, Guo B, Zhu B. Stroma-derived brin-
ogen-like protein 2 activates cancer-associated broblasts to promote tumor growth in
lung cancer. Int J Biol Sci. 2017 Jun 1;13(6):804.
298. Yang M, Wei Z, Feng M, Zhu Y, Chen Y, Zhu D. Pharmacological inhibition and genetic
knockdown of BCL9 modulate the cellular landscape of cancer-associated broblasts
in the tumor-immune microenvironment of colorectal cancer. Front Oncol. 2021 May
5;11:603556.
299. Aboulkheyr Es H, Zhand S, Thiery JP, Warkiani ME. Pirfenidone reduces immune-
suppressive capacity of cancer-associated broblasts through targeting CCL17 and
TNF-be
ta. Integr Biol. 2020 Jul;12(7):188–197.
300. Zhang L, Zhang Y, Wang X, Zhou Y, Qi J, Gu L, Zhao Q, Yu R, Zhou X. A trojan-
horse-like biomimetic Nano-NK to elicit an immunostimulatory tumor microenviron-
ment for enhanced GBM chemo-immunotherapy. Small. 2023 Nov;19(44):2301439.
81DOI: 10.1201/9781003405023-4
4
Redefining the Role of
Endothelial Cells in the
Tumor Microenvironment
Suchandra Chowdhury and Sanjima Pal
4.1 INTRODUCTION
Cancer is a complex ecosystem, involving a wide range of noncancerous cells and
their numerous interactions within the tumor. The noncancerous cells form the
tumor microenvironment (TME) which is a complicated and continuously develop-
ing milieu nourishing and nurturing the cancerous cells. Multiple cytokines, che-
mokines, and other factors released by the cancer cells functionally construct the
TME for a robust survival of the tumor (Hinshaw and Shevde, 2019). In addition
to the cellular components of the TME, namely, the stromal cells like broblasts,
endothelial cells (ECs), neurons, adipocytes, and immune cells, the noncellular com-
ponents comprise the extracellular matrix (ECM) and many soluble biomolecules,
such as chemokines, cytokines, growth factors, and extracellular vesicles (Xiao and
Yu, 2021). This chapter elucidates the currently emergent pathophysiological aspects
of TECs with special attention on their potential role as regulators of immune cell
function in the tumor microenvironment and the signicance of associated factors in
the development of novel cancer therapeutics.
4.2 ENDOTHELIAL CELLS (ECs)
Endothelial cells (ECs) are the components of the circulatory system, where they form
the inner monolayered lining of blood and lymphatic vessels. They form a semiper-
meable membrane separating blood or lymph within vessels from their surrounding
tissues. ECs differentiated from angioblasts (EC progenitors having a mesodermal
origin) with expression of specic transcription factors (De Val and Black, 2009).
ECs are dynamic in their morphology structure and function and known to be exhibit
heterogeneity. ECs from different vasculatures of the same individual are reported
to express different surface antigens, receptors, and surface markers and can even
produce different reactions to the same stimulus (Galley and Webster, 2004; Mai
et al., 2013). For example, morphological and functional heterogeneity is contrib-
uted by the presence of different glycocalyx such as proteoglycans, glycosamino-
glycan side chains, sialoproteins, glycolipids, and proteoglycans and associated with
the luminal side of ECs. Glycocalyx is the vessel component all type organs and
82 The Dynamics of Tumor Microenvironment and Therapeutic Targets
imparts structural and functional diversity as well as plays a major role in perme-
ability, ltration, oxygen, and nutrient delivery of ECs to cells (Reiterer and Branco,
2020). The universally accepted responsibilities of these ECs in the homeostasis of
the body’s physiology are to safeguard transport logistics, control vascular perme-
ability, and regulate vascular tone, the maintenance of blood uidity, permeability,
angiogenesis, and both innate and adaptive immunity. ECs mostly undergo a dor-
mant state following morphogenesis and are expressed transiently on physiological
requirements. However, during tumor progression, the angiogenic switch is found to
be active all the time, leading to sprouting and formation of new blood vessels from
ECs of existing vessels. The process happens to supply nourishment and oxygen
to the proliferating cells and further to expel metabolic waste and carbon dioxide.
ECs are metabolically active and exhibit extraordinary heterogeneity in structure and
function, which varies with space and time and in health and in disease condition.
The heterogeneity of the ECs is mediated by the mechanisms of microenvironment
and epigenetics (Aird, 2012; Sturtzel, 2017).
Other than serving as a barrier, ECs have multiple physiological functions, like
regulation of metabolic homeostasis, vascular tone, hemodynamic or blood ow,
vascular permeability, hemostasis, blood coagulation, and cell trafcking. The
metabolic homeostasis by ECs involves the transport of glucose, amino acids, fatty
acids, etc. by expressing specic transporters. ECs communicate with each other
and with their surrounding environment to form a branched vascular network. Due
to the indispensable role of these ECs in nourishing all living cells of the body, it is
predictable that structural or functional vessel abnormalities contribute to many dis-
eases. Insufcient maintenance or growth of vessel causes ischemia in diseases like
myocardial infarction, stroke, and neurodegenerative or obesity-associated disorders,
while extensive vascular growth or remodeling promotes cancer and other inamma-
tory disorders. Vessels lined by ECs are also used as routes for metastasis (Potente
et al., 2011). Vascular tone is the regulation of vasodilation and vasoconstriction
mediated by factors secreted from ECs, such as nitric oxide, prostacyclins, endo-
thelin, and leukotrienes, which have a role on vascular smooth muscles and in turn
regulate blood pressure and blood ow. ECs are involved in host immune defense
and inammatory response by orchestrating cell–cell communication by secreting
cytokines. In normal physiological conditions, ECs express anticoagulant factors like
inhibitors of the tissue factor pathway, and thrombomodulin to inhibit the activation
of coagulant factors like thrombin, facilitating blood ow. In contrast, in case of per-
turbation in blood vessels, direct expression of inducing tissue factors by ECs leading
to activation of pro-coagulants to initiate coagulation to prevent internal bleeding.
Other than blood ow, due to the location of ECs, they recognize the microbial infec-
tion in the blood and activate downstream immune response (Mai et al., 2013; Galley
and Webster, 2004).
4.3 TUMOR ENDOTHELIAL CELLS (TECs)
Tumor ECs (TECs) are morphologically different from their normal counterpart.
They generally have multiple fenestrations, uneven surfaces, and intraluminal
83Endothelial Cells in Tumor Microenvironment
projections, and relaxed intercellular junctions forming multilayered endothelia, fea-
tures facilitating vascular leakage and restricted blood ow. In contrast to distinct
gene expression proles exhibited by the vascular ECs of different tissues, TECs dis-
play signicant inter- and intratumoral molecular heterogeneity. The functional role
of TECs is multifaceted as they are not only important for initiating and maintaining
tumors but are key participants in metastasis as well. The recent scientic advances
have highlighted the importance of several angiogenic switches governed by some
countervailing factors necessary for propagating or counteracting angiogenesis, thus
opening new avenues to study and to counter TECs. The TECs display enhanced pro-
liferative, migratory, and tube-formation capabilities in response to growth factors
and cytokines, compared with nontumor ECs. Additionally, these cells are tolerant
to senescence and grow ex vivo in serum-free conditions probably due to the upregu-
lation of growth factor and cytokine receptors like vascular endothelial growth fac-
tor receptors (VEGFRs) (Potente et al., 2011; Aird et al., 2012). Unlike the normal
ECs, TECs may express epidermal growth factor receptor (EGFR) and proliferate
in response to epidermal growth factor (EGF) (Amin et al., 2006). They demon-
strate constitutive activation of PI3K–AKT signaling, promoting tumor cell survival
and resistance to apoptosis. TECs also exhibit gene and chromosomal abnormalities
like aneuploidy, translocations, and supernumerary centrosomes, which accumulate
genetic mutations (Hida et al., 2016).
TECs are hyper-glycolytic and essentially use aerobic glycolysis to meet their
energy requirements and are more resistant to the cytotoxic drugs than normal
ECs (Potente and Carmeliet, 2017). They produce reactive oxygen species (ROS)
in response to oxidative stress and are directly exposed to ROS released by tumor-
inltrating inammatory cells and cancer cells. Additionally, hypoxia blocks the cel-
lular DNA repair system. Both the processes, teamed with the high proliferation
rate of tumor ECs, can be directly mutagenic and promote genetic variability in
TECs (Kim and Byzova, 2014). TECs express relatively decreased levels of adhe-
sion molecules, which are responsible for an impaired barrier function. They also
express enhanced levels of inhibitory immune checkpoint molecules that contribute
to immunosuppression (De Palma et al., 2017; Amersfoort et al., 2022).
4.4 HETEROGENEITY OF TECs
The TECs exhibit a notable heterogeneity and plasticity. The EC lining of tumor
blood vessels usually develops from the propagation of normal ECs from the adja-
cent tissues. Therefore, the principal determinant of phenotypic heterogeneity of
the TECs is the surrounding microenvironment. The TECs in the newly formed
blood vessels are exposed to an exclusive combination of extracellular signals like
hypoxia, acidic pH, variable blood ow, hypoglycemia, and several soluble media-
tors released by the tumor cells and stromal cells, including growth factors (e.g.,
vascular endothelial growth factor, broblast growth factor-2, hepatocyte growth
factor, and angiopoietin) and cytokines (e.g., CXCL8 and CXCL1). The disposition
of these paracrine signals is induced by underlying activation of oncogenes and/or
the inactivation of tumor suppressor genes in the tumor cells. The TECs in return
84 The Dynamics of Tumor Microenvironment and Therapeutic Targets
release factors that inuence tumor growth. The tumor endothelium is devoid of an
organized basement membrane and exhibits contact with the pericytes. As a result,
these TECs do not receive signal inputs. The second factor determining the pheno-
typic heterogeneity of the TECs is epigenetic factor. When the tumor blood vessels
develop from different vascular beds, their original site-specic epigenetic footprint
is retained although the cells are exposed to the unique TME (Aird et al., 2012; De
Palma et al., 2017).
4.5 MODULATION OF TEC CHARACTERISTICS BY THE TME
The TME helps in the development of the abnormal characteristics of the TECs.
When tumor cells and ECs are cocultured, it leads to upregulation of pro-
angiogenic genes and phenotypic changes, which hints toward the contribution of
the pro-angiogenic factors secreted by the tumors. Another mechanism responsi-
ble for conferring pro-angiogenic phenotype is hypoxia. Fast-growing tumors will
exhaust their source of oxygen and nutrients, leading to a hypoxic and necrotic
milieu. One of the main causes of hypoxia is the abnormalities of the TECs that
make the tumor vasculature leaky, resulting in high tissue pressure inside the
tumor and compression of the tumor vessels (Sato, 2011). Enhanced production of
VEGF, along with vascular permeability and genetic instability in the TECs, is
triggered by hypoxia. The subsequent reduction in blood ow in the tumor vessels
further lowers the supply of nutrient and oxygen, imposing physiological stress on
the tumor. Hypoxia also induces the migration of bone marrow progenitor cells
to the leading edge of necrotic tumors, promoting tumor revascularization (Gao
et al., 2009; Hida et al., 2016). The platelets also secrete pro- and anti-angiogenic
mediators, which bind to the ECs to regulate angiogenesis and vascular integrity
(Braun et al., 2021).
4.6 IMMUNOMODULATORY ENDOTHELIAL CELLS
Modern single-cell studies have identied specic EC subtypes that express sig-
nature genes indicative of phagocytosis or scavenging, antigen presentation, and
immune cell recruitment. These distinct subtypes of ECs, having tissue- and vessel-
type-specic immunomodulatory roles, are collectively termed immunomodula-
tory ECs (IMECs). Some subtypes of ECs display features characteristic of immune
cells, which also include the expression of co-stimulatory and co-inhibitory receptor
(Carman and Martinelli, 2015).
The liver sinusoidal ECs (LSECs) present cancer-cell-derived apoptotic bodies to
naive CD8+ T cells. These LSECs act as semi-professional antigen-presenting cells
(APCs), thereby impairing the differentiation of naive CD8+ T cells, preventing
them from being functional effector cytotoxic T cells (CTLs) that kill cancer cells.
The LSECs also induce immunologic tolerance in hepatocellular carcinoma. Thus,
these LSECs hamper tumor immunity and affects disease outcome (Yu et al., 2019;
Amersfoort et al., 2022).
85Endothelial Cells in Tumor Microenvironment
In lung cancer, tumor ECs (TECs) are also immunosuppressive since they dis-
play diminished expression of antigen-presenting molecules, intercellular adhe-
sion molecule 1 (ICAM1), and other cytokines and chemokines compared with
normal lung ECs. Moreover, immunosuppressive features of lung TECs embrace
improved expression of FAS ligand (FASL), which induce CD8+ T cell apop-
tosis, and high levels of inhibitory molecules such as program death ligand 1
(PDL1) (Lambrechts et al., 2018; Klein, 2018; Liu et al., 2020). In Wilms tumors,
renal TECs upregulate ACKR1 transcription, a marker of venular endothelium
promoting tissue migration of immune cells (Young et al., 2018; Amersfoort
et al., 2022).
The angiogenic ECs have phenotypic similarity, while other EC subtypes
are different. Predictive interactome analysis reveals receptor–ligand interac-
tions between ECs and immune cells, proposing the association of breast can-
cer ECs in immune responses. The capillary EC subtype (lipid processing EC
[LIPEC]), which expresses genes involved in lipid processing, is more profuse in
peritumoral breast tissue. Such interactions can help in immunotherapy (Geldhof
et al., 2022) (Figure 4.1).
FIGURE 4.1 EC-mediated remodeling in the TME ecosystem. Tumor endothelial cells
(TECs) are located at the interface between the tumor microenvironment (TME) and blood
vessels. The most critical function of TECs is to promote tumor growth and metastasis by
creating a complex network of cells, blood vessels, and other factors within the TME.