Circulating Tumor Cells in Metastatic Cascade: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Kwan T Chow.

Immune System in Non-Tumor Microenvironment

Circulating tumor cells (CTCs) are a heterogeneous population of tumor cells that have shed from a tumor into the lymphatics and vasculature, ultimately disseminating into blood circulation. Circulating tumor cells are a key player in cancer metastasis, a multi-step and complex process that involves (1) local invasion of primary tumor cells into adjacent tissue; (2) intravasation (trans-endothelial migration into nearby blood vessels); (3) circulation (transient travel and survival in the circulatory system as CTCs); (4) extravasation; (5) colonization. To successfully metastasize, CTCs must evade immune surveillance at every step once they leave the immunosuppressive tumor microenvironment. On the other hand, immune cells can promote or inhibit tumorigenesis, depending on the cell type and context.

  • circulating tumor cells (CTCs)
  • metastasis cascade
  • immune cells

1. Intravasation

Intravasation is the process by which cancer cells shed from primary or metastatic deposits and traverse the endothelium to enter the bloodstream, thus, forming Circulating tumor cells (CTCs) and pioneering the metastatic cascade. Immune cells that interact with CTCs during the initial stages of metastasis include neutrophils, natural killer (NK) cells, monocytes, macrophages, and T lymphocytes.

1.1. Neutrophils

The recruitment of neutrophils by primary tumor is implicated in the elevated rate of intravasation in vivo [51][1]. In breast cancer patients, as well as in mouse models, neutrophils facilitate the intravasation of tumor cells by forming CTC-neutrophil clusters, which express higher levels of positive regulators of cell cycle and DNA replication programs than CTCs alone, leading to increased metastatic propensity and poor prognosis [22][2]. Activated neutrophils secrete neutrophil extracellular traps (NETs), which contain factors such as matrix-metalloprotein-9 (MMP-9), neutrophil elastase (NE), and cathepsin G (CG) that promote extracellular matrix (ECM) degradation and cellular aggregation. Evidently, these factors can promote CTC migration and invasion while enhancing proliferation and anti-apoptosis traits of CTCs at the same time [52][3]. Accordingly, transcriptomic analysis on peripheral blood leukocytes from treatment-naïve renal cell carcinoma patients indicated that NET formation, as indicated by elevated expression of NET formation regulators, promotes CTC viability [53,54][4][5]. Another study also demonstrated that neutrophil activation in the blood correlates with CTC survival [54][5]. In early-stage breast cancer patients, increased levels of NETs in the blood have been proposed as a biomarker that specifically predict the chronic risk of liver metastases [53][4].

1.2. NK Cells

A study by Santos et al. demonstrated a close link between the number of CTCs and the cytotoxic activity of NK cells in the blood of breast, colorectal, and prostate cancer patients [55][6]. The NK cells from patients with a high number of CTCs showed diminished cytotoxicity, as compared to those isolated from patients with a low number of CTCs. This is consistent with an earlier study, where mice with low NK cell activity showed enhanced blood-borne tumor cell survival and increased incidence of metastasis [56,57][7][8].

1.3. Monocytes and Macrophages

Monocytes and macrophages have been reported to aid in intravasation via myriad mechanisms. A three-cell complex, termed “tumor microenvironment of metastasis doorway”, composed of a perivascular macrophage, a tumor cell, and an endothelial cell, is found to act as a gateway for tumor cell hematogenous dissemination. Intravital high-resolution microscopy revealed that perivascular macrophages promote transient vascular permeability by interacting with endothelial cells, via VEGFA signaling, and consequently facilitate the intravasation of tumor cells [58,59,60][9][10][11]. In addition, tumor- or CTC-educated macrophages influence almost all the steps of the metastatic cascade, such as accelerating invasion, intravasation, survival in the circulation, tumor cell arrest, extravasation, as well as durable growth at distant sites [61,62][12][13]. Solid tumor-based studies suggested that CTCs intravasate into the circulatory system along with TAMs [63,64][14][15]. Additional clinical evidence of the continued interaction of macrophages with tumor cells was found in the blood circulation of cancer patients. Despite the rarity of cell types, and the shear stresses within the vascular circulation, circulating CAMLs and macrophages with pro-angiogenic capacity have been found to migrate through the circulation, attached to CTCs in 10% of late-stage patients with breast, pancreatic, or prostate cancers [11][16]. Together, these lines of evidence demonstrated a critical role of macrophages in metastatic intravasation.
Besides immunosurveillance, macrophages are also involved in the establishment of the premetastatic niche, particularly in the lungs. Using an intravital two-photon lung imaging system, CTCs lodged in the capillaries of the lungs were found to shed microparticles into the vasculature, driven by high shear forces within seconds of arrival. Following CTC entry, myeloid cells, such as monocytes, macrophages, neutrophils and dendritic cells (DCs), ingest these large microparticles. Of note, tumor-ingesting macrophages display an activated phenotype and pro-metastatic function, while lung-resident conventional dendritic cells showed anti-metastasis effects [65][17]. These findings demonstrated the complex interplay between CTCs and various immune cells.

1.4. T Cells

There are limited investigations into the role of CD4+ helper T cells and CD8+ cytotoxic T cells in the immune surveillance of CTCs. As such, receptor activator of nuclear kappa-B ligand (RANKL) expressed by tumor-infiltrating CD4+ T cells are thought to stimulate RANK, expressed on CTC from breast cancer, to enhanced intravasation [66,67][18][19]. In a more recent study, CD4+ T cells were found to be unexpectedly involved in vasculature and immune reprogramming, thereby contributing to impeding cancer cell intravasation [68][20]. In that study, CD4+ T cell deficiency resulted in reduced immune responses, lower expression of good-prognosis angiogenesis genes (GPAGs), and higher expression of poor-prognosis angiogenesis genes (PPAGs), defined by the author. Loss of CD4+ T cells also altered pathways and genes that regulate vessel normalization. Two studies have illustrated the safeguarding role of CD8+ T cells in intravasation. Increased CTCs were found in CD8 knockout mice with breast cancer, demonstrating that loss of cytotoxic T cells promoted CTCs survival, as well as increased intravasation [68,69][20][21]. However, the mechanisms by which interaction of CTCs and T lymphocytes contribute to intravasation have not been fully clarified. Therefore, understanding the role of different T cell subsets in different stages of metastasis cascade is necessary to validate the above findings.

2. CTC Survival in Circulation

Most CTCs undergo apoptosis, owing to physical stress, through shear and tear in the circulation and anoikis [70][22]. Further, immune cytotoxicity eliminates the majority of CTCs in the blood [71][23], and deprivation of growth and survival factors outside the tumor niche also contribute to CTC death [72][24]. Despite these harsh survival conditions, CTCs can survive in the blood and contribute to metastasis to secondary sites by mechanisms such as cellular mutation, cytokine and growth factor stimulation, and interactions with surrounding cell types [30,73][25][26]. Here, we focus on the vast interactions between CTCs and immune cells during their voyage from the blood to dormancy and colonization in secondary sites.
The small number of CTCs that survive are able to hijack immune cells and improve their survival odds. These resistant CTCs gain enhanced metastatic seeding capability by utilizing immune cells to amplify certain traits, such as migration ability and invasiveness, as well as to modify and adapt to unfavorable circumstances. Some of the major immune cell types that interact with CTCs in circulation include neutrophils, monocytes/macrophages, lymphocytes, and NK cells [30,74][25][27].

2.1. Neutrophils

CTC–neutrophil clusters are one of the common CTC clusters found in blood. As first responders, neutrophils are attracted to primary tumors and CTCs that produce granulocyte colony stimulating factor (G-CSF) and other neutrophil stimulating cytokines [22,75][2][28]. Initially, neutrophils induce inflammation and release hydrogen peroxide that are cytotoxic against CTCs [76][29]. However, as the cancer progresses, immunosuppressive TGFβ1 that originates from the primary tumor microenvironment, and platelets, can induce N2 neutrophil polarization, which aids in CTC survival and epithelial–mesenchymal transition (EMT) [77,78,79][30][31][32]. Additionally, CTCs can develop resistance towards neutrophil-mediated cell death, through mutation in the TLE1 gene that promotes NFkB-mediated cancer progression [80][33]. Neutrophils in CTC clusters are found to express adhesion factors, such as VCAM-1 and intracellular adhesion molecule 1 receptor (ICAM-1), which likely explains how neutrophils form close “piggyback” adhesions with CTCs [81,82][34][35]. This close interaction between CTCs and neutrophil enhances the activation of proliferative pathways in CTCs via crosstalk of cytokines, such as IL-6 and IL-1β, from neutrophils [75][28]. In addition to the pro-survival effects mentioned previously, NETs can serve as a protective cloak that bind to CTCs, via β1-integrin, to protect them from shear stress and immune cytotoxicity in the blood [83][36].

2.2. Monocytes and Macrophages

Monocytes are another abundant circulating immune cell type found in CTC clusters. They patrol within the blood circulation, where they eliminate cellular debris and are a significant mediator of the inflammatory processes. Monocytes can present themselves with a diverse subset of phenotypes and functions, depending on the external stimuli in their immediate environment [84][37]. Shibuya et al. demonstrated that tissue repair promoting Ym1+ Ly6Chi monocytes promoted CTC-mediated lung metastasis in the presence of systemic inflammation [85][38], highlighting an important role for immunosuppressive monocytes in supporting CTC metastasis. Monocytes can mature into macrophages that acquire the ability to phagocytose larger targets, including CTCs. In fact, macrophages can detect and distinguish foreign cells from self-cells through CD47, a cell surface glycoprotein that serves as a “do not eat me” signal. Furthermore, CTCs and secondary metastases are found to express high levels of CD47, suggesting that they acquire better survival advantages in blood circulation and secondary growth sites, likely by evading immunogenic responses [86][39].
Aside from evading phagocytosis, CTCs also take advantage of macrophages in a direct manner, through cytokine crosstalk. Tumor cells release colony stimulating factor 1 (CSF1) that recruits macrophages and polarizes them towards tissue repair-promoting M2 TAMs, which, in turn, produce growth factors like epidermal growth factor (EGF) that further stimulates tumor cells to produce CSF-1, thus, forming a positive feedback loop [87,88][40][41].

2.3. T Cells

Effector CD4+ and CD8+ T lymphocytes exert hostile responses toward CTCs in the circulation. Further, PD-L1 expression on T cells has been found to correlate with increased CTC survival in metastatic genitourinary cancer and advanced non-small cell lung cancer (NSCLC), along with lower CD4+ and CD8+ T cell numbers [89,90][42][43]. It is suggested that PDL1+ CTCs are able to suppress T cell activation and, thereby, dampen the immune response against CTCs in the blood [91][44]. In another study, CTCs expressing elevated levels of T cell programmed cell death Fas ligand were detected in breast cancer patients, causing increased apoptosis of T cells in circulation [92][45]. These observations indicate that CTCs may depend on T cell deactivation and apoptosis to prolong their survival in circulation, as supported by their negative correlation with CD4+ and CD8+ T cell numbers and shorter overall patient survival [1][46].
Regulatory T cells (Tregs) are an immunosuppressive T lymphocyte subset that negatively regulate cytotoxic T lymphocyte activation [93][47]. The CTCs preferentially recruit circulating Tregs through the release of chemokines, such as CCL5, CCL22, CCL17, CXCL9 and CXCL10 [94][48]. Subsequently, circulating Tregs are activated by tumor-derived suppressive factors (TDSFs), including IL-10 and TGFβ1, to promote an immunosuppressive environment that limits T effector functions and contributes to CTC survival [95,96][49][50]. In addition, the RANKL, secreted by Tregs, can help promote tumor migration in RANK+ CTCs [66,97][18][51]. Evidently, CTC counts are positively correlated to circulating Tregs in various cancers, such as inflammatory breast cancer, hepatocellular carcinoma (HCC), and NSCLC [1,98,99][46][52][53].

2.4. NK Cells

Similar to T lymphocytes, NK cells play a pivotal role in restricting CTC survival and metastasis through direct interception in circulation. The NK cells can initiate the indirect killing of CTCs through the secretion of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that binds to apoptotic receptors on tumor cells [100,101][54][55]. Resistant CTCs are able to mitigate this by downregulating their death receptor 5 (DR5) expression on the cell surface [102][56]. The secretion of granzyme and perforin from NK cells represents another form of cytotoxicity towards CTCs that is deemed more effective, capable of eliminating up to 80% of CTCs and slowing down metastatic spread [103][57]. Low NK cell numbers are indicated to be an independent risk factor for CTCs and their progression [1][46]. In recent studies, CTC clusters were shown to evade NK cytotoxicity much more effectively than single CTCs [104][58]. Notably, NK cell-mediated cytotoxicity is suggested to be more potent towards CTCs with partial mesenchymal-like traits, though further insight is still required to comprehend the dynamic interaction between CTCs and NK cells from the blood to metastatic colonization [105][59].

3. Extravasation and Colonization

As CTCs roam in the bloodstream, a small percentage of these cells will get arrested in tight capillaries, which may be a prerequisite for extravasation [106][60]. The CTC clusters have better odds at initiating this process due to the large size that can get embedded in tight spaces for longer periods [107][61]. The cancer infiltration process can be promoted through several factors, including CTC expression of surface receptors and integrins for attachment, mechanical and physical pressure, chemotactic gradient from certain secondary sites, and with aid from immune cells in clusters [108][62]. Here, we focus on how immune cells support and mediate the extravasation and colonization of CTCs into secondary metastasis sites.
Upon arrest, leukocytes in CTC clusters interact with endothelial cells lining the vasculature that are essential for endothelial attachment. During this process, tumor cells secrete factors such as IL-8 to promote the leukocyte expression of adhesion receptors like β2-integrin, that can bind directly to ICAM-1 and E-selectin, present on endothelial cells [109][63]. For instance, tumor cells that are entrapped within NETs from neutrophils act as passengers, whereby neutrophils that express CD11a (LFA1) and CD11b (Mac-1) are able to interact with ICAM-1 on endothelial cells [110][64]. At the same time, tumor cells produce factors that upregulate these adhesion receptors and promote migration potential in neutrophils by delaying apoptosis [111][65]. Monocytes and TAMs, on the other hand, secrete cytokine and chemotactic factors, such as VEGF, TGFβ1, and CCL2, to increase vessel permeability and to destroy endothelial tight junctions, thereby mediating trans-endothelial migration [112,113][66][67]. Tumor cells are also capable of following the “microtracks” generated by macrophages, as they cross the endothelial border [114][68].
Tumor cells that infiltrated secondary sites, hereby termed disseminated tumor cells (DTCs), have to overcome immune surveillance at the secondary site and undergo mesenchymal–epithelial transition (MET) to gain the capacity to colonize upon the local niche. In this regard, immune surveillance at different organs poses different threats, depending on the local immune composition. In breast cancer/prostate cancer-mediated bone metastases, tumor cells actively modulate the local immune niche by secreting extracellular vesicles (EVs) and factors, including VEGF, IL-6, and IL-8, that promote osteoclast differentiation and activate osteoblasts to support osteoclast activities, which causes osteolysis. Subsequently, these activated bone cells also secrete tumor growth promoting factors like TGFβ1, to advocate tumor growth and, ultimately, form a positive feedback loop [115][69]. These interactions enable tumor cells to undergo “osteomimicry”, where they express bone-related genes to adapt and expand upon bone sites [116][70]. T cells and NK cells play a prominent role in eliminating DTCs in metastatic niches [117][71]. In lung metastasis, tumors modify pre-metastatic niche by recruiting neutrophils to the lungs via immune–cancer crosstalk [118][72]. These neutrophils suppress T cell cytotoxicity via inducible nitric oxide synthase (iNOS) expression [119][73]. Furthermore, DTCs with altered antigen presentation characteristics are capable of minimizing T cell and NK cell cytotoxicity. In such cases, PD-L1 expression and downregulation of major histocompatibility complex I (MHC I) are modifications that allow tumors to evade NK and T cell-mediated killing, though NK cells may still recognize tumor cells with abnormally low MHC I levels [120,121][74][75]. Additionally, DTCs may recruit immunosuppressive myeloid cells to suppress NK cell activity [122][76]. For DTCs to fully integrate into the local niche, MET process is necessary for tumors to revert into epithelial forms. Moreover, TAMs secrete IL-35 that facilitates MET in tumor cells, through the activation of JAK2–STAT6-GATA3 signaling [123][77]. In the late stage of metastasis, DTCs that survive and have undergone EMT expand to form overt metastases upon acquiring sufficient growth signals in a favorable condition.

References

  1. Bekes, E.M.; Schweighofer, B.; Kupriyanova, T.A.; Zajac, E.; Ardi, V.C.; Quigley, J.P.; Deryugina, E.I. Tumor-recruited neutrophils and neutrophil TIMP-free MMP-9 regulate coordinately the levels of tumor angiogenesis and efficiency of malignant cell intravasation. Am. J. Pathol. 2011, 179, 1455–1470.
  2. Szczerba, B.M.; Castro-Giner, F.; Vetter, M.; Krol, I.; Gkountela, S.; Landin, J.; Scheidmann, M.C.; Donato, C.; Scherrer, R.; Singer, J.; et al. Neutrophils escort circulating tumour cells to enable cell cycle progression. Nature 2019, 566, 553–557.
  3. Cools-Lartigue, J.; Spicer, J.; Najmeh, S.; Ferri, L. Neutrophil extracellular traps in cancer progression. Cell Mol. Life Sci. 2014, 71, 4179–4194.
  4. Yang, L.; Liu, Q.; Zhang, X.; Liu, X.; Zhou, B.; Chen, J.; Huang, D.; Li, J.; Li, H.; Chen, F.; et al. DNA of neutrophil extracellular traps promotes cancer metastasis via CCDC25. Nature 2020, 583, 133–138.
  5. Wen, L.; Guo, L.P.; Zhang, W.; Li, Y.J.; Jiang, W.X.; Di, X.B.; Ma, J.H.; Feng, L.; Zhang, K.T.; Shou, J.Z. Cooperation Between the Inflammation and Coagulation Systems Promotes the Survival of Circulating Tumor Cells in Renal Cell Carcinoma Patients. Front. Oncol. 2019, 9.
  6. Santos, M.F.; Mannam, V.K.; Craft, B.S.; Puneky, L.V.; Sheehan, N.T.; Lewis, R.E.; Cruse, J.M. Comparative analysis of innate immune system function in metastatic breast, colorectal, and prostate cancer patients with circulating tumor cells. Exp. Mol. Pathol. 2014, 96, 367–374.
  7. Hanna, N. Role of natural killer cells in control of cancer metastasis. Cancer Metastasis Rev. 1982, 1, 45–64.
  8. Hanna, N.; Fidler, I.J. Role of natural killer cells in the destruction of circulating tumor emboli. J. Natl. Cancer Inst. 1980, 65, 801–809.
  9. Wyckoff, J.B.; Wang, Y.; Lin, E.Y.; Li, J.F.; Goswami, S.; Stanley, E.R.; Segall, J.E.; Pollard, J.W.; Condeelis, J. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res. 2007, 67, 2649–2656.
  10. Harney, A.S.; Arwert, E.N.; Entenberg, D.; Wang, Y.; Guo, P.; Qian, B.Z.; Oktay, M.H.; Pollard, J.W.; Jones, J.G.; Condeelis, J.S. Real-Time Imaging Reveals Local, Transient Vascular Permeability, and Tumor Cell Intravasation Stimulated by TIE2hi Macrophage-Derived VEGFA. Cancer Discov. 2015, 5, 932–943.
  11. Ginter, P.S.; Karagiannis, G.S.; Entenberg, D.; Lin, Y.; Condeelis, J.; Jones, J.G.; Oktay, M.H. Tumor Microenvironment of Metastasis (TMEM) Doorways Are Restricted to the Blood Vessel Endothelium in Both Primary Breast Cancers and Their Lymph Node Metastases. Cancers 2019, 11, 1507.
  12. Kitamura, T.; Qian, B.Z.; Pollard, J.W. Immune cell promotion of metastasis. Nat. Rev. Immunol. 2015, 15, 73–86.
  13. Jiang, W.G.; Sanders, A.J.; Katoh, M.; Ungefroren, H.; Gieseler, F.; Prince, M.; Thompson, S.K.; Zollo, M.; Spano, D.; Dhawan, P.; et al. Tissue invasion and metastasis: Molecular, biological and clinical perspectives. Semin. Cancer Biol. 2015, S244–S275.
  14. Roussos, E.T.; Balsamo, M.; Alford, S.K.; Wyckoff, J.B.; Gligorijevic, B.; Wang, Y.; Pozzuto, M.; Stobezki, R.; Goswami, S.; Segall, J.E.; et al. Mena invasive (MenaINV) promotes multicellular streaming motility and transendothelial migration in a mouse model of breast cancer. J. Cell Sci. 2011, 124, 2120–2131.
  15. Condeelis, J.; Pollard, J.W. Macrophages: Obligate partners for tumor cell migration, invasion, and metastasis. Cell 2006, 124, 263–266.
  16. Adams, D.L.; Martin, S.S.; Alpaugh, R.K.; Charpentier, M.; Tsai, S.; Bergan, R.C.; Ogden, I.M.; Catalona, W.; Chumsri, S.; Tang, C.-M. Circulating giant macrophages as a potential biomarker of solid tumors. Proc. Natl. Acad. Sci. USA 2014, 111, 3514–3519.
  17. Headley, M.B.; Bins, A.; Nip, A.; Roberts, E.W.; Looney, M.R.; Gerard, A.; Krummel, M.F. Visualization of immediate immune responses to pioneer metastatic cells in the lung. Nature 2016, 531, 513–517.
  18. Tan, W.; Zhang, W.; Strasner, A.; Grivennikov, S.; Cheng, J.Q.; Hoffman, R.M.; Karin, M. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 2011, 470, 548–553.
  19. DeNardo, D.G.; Barreto, J.B.; Andreu, P.; Vasquez, L.; Tawfik, D.; Kolhatkar, N.; Coussens, L.M. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 2009, 16, 91–102.
  20. Tian, L.; Goldstein, A.; Wang, H.; Ching Lo, H.; Sun Kim, I.; Welte, T.; Sheng, K.; Dobrolecki, L.E.; Zhang, X.; Putluri, N.; et al. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature 2017, 544, 250–254.
  21. Joseph, R.; Soundararajan, R.; Vasaikar, S.; Yang, F.; Allton, K.L.; Tian, L.; den Hollander, P.; Isgandarova, S.; Haemmerle, M.; Mino, B.; et al. CD8(+) T cells inhibit metastasis and CXCL4 regulates its function. Br. J. Cancer 2021, 125, 176–189.
  22. Paoli, P.; Giannoni, E.; Chiarugi, P. Anoikis molecular pathways and its role in cancer progression. Biochim. Et Biophys. Acta 2013, 1833.
  23. Luzzi, K.J.; MacDonald, I.C.; Schmidt, E.E.; Kerkvliet, N.; Morris, V.L.; Chambers, A.F.; Groom, A.C. Multistep nature of metastatic inefficiency: Dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am. J. Pathol. 1998, 153, 865–873.
  24. Strilic, B.; Offermanns, S. Intravascular Survival and Extravasation of Tumor Cells. Cancer Cell 2017, 32, 282–293.
  25. Ward, M.P.E.; Kane, L.E.; Norris, L.A.; Mohamed, B.M.; Kelly, T.; Bates, M.; Clarke, A.; Brady, N.; Martin, C.M.; Brooks, R.D.; et al. Platelets, immune cells and the coagulation cascade; friend or foe of the circulating tumour cell? Mol. Cancer 2021, 20, 59.
  26. Wang, W.-C.; Zhang, X.-F.; Peng, J.; Li, X.-F.; Wang, A.-L.; Bie, Y.-Q.; Shi, L.-H.; Lin, M.-B.; Zhang, X.-F. Survival Mechanisms and Influence Factors of Circulating Tumor Cells. BioMed Res. Int. 2018, 2018, 6304701.
  27. Zhong, X.; Zhang, H.; Zhu, Y.; Liang, Y.; Yuan, Z.; Li, J.; Li, J.; Li, X.; Jia, Y.; He, T.; et al. Circulating tumor cells in cancer patients: Developments and clinical applications for immunotherapy. Mol. Cancer 2020, 19, 15.
  28. Iriondo, O.; Yu, M. Unexpected Friendship: Neutrophils Help Tumor Cells En Route to Metastasis. Dev. Cell 2019, 49, 308–310.
  29. Granot, Z.; Henke, E.; Comen, E.A.; King, T.A.; Norton, L.; Benezra, R. Tumor Entrained Neutrophils Inhibit Seeding in the Premetastatic Lung. Cancer Cell 2011, 20, 300–314.
  30. Masucci, M.T.; Minopoli, M.; Carriero, M.V. Tumor Associated Neutrophils. Their Role in Tumorigenesis, Metastasis, Prognosis and Therapy. Front. Oncol. 2019, 9.
  31. Grosse-Steffen, T.; Giese, T.; Giese, N.; Longerich, T.; Schirmacher, P.; Hänsch, G.M.; Gaida, M.M. Epithelial-to-mesenchymal transition in pancreatic ductal adenocarcinoma and pancreatic tumor cell lines: The role of neutrophils and neutrophil-derived elastase. Clin. Dev. Immunol. 2012, 2012, 720768.
  32. Yan, M.; Jurasz, P. The role of platelets in the tumor microenvironment: From solid tumors to leukemia. Biochim Biophys Acta 2016, 1863, 392–400.
  33. Ramasamy, S.; Saez, B.; Mukhopadhyay, S.; Ding, D.; Ahmed, A.M.; Chen, X.; Pucci, F.; Yamin, R.; Wang, J.; Pittet, M.J.; et al. Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway. Proc. Natl. Acad. Sci. USA 2016, 113, 1871–1876.
  34. Guo, B.; Oliver, T.G. Partners in Crime: Neutrophil-CTC Collusion in Metastasis. Trends Immunol 2019, 40, 556–559.
  35. Taftaf, R.; Liu, X.; Singh, S.; Jia, Y.; Dashzeveg, N.K.; Hoffmann, A.D.; El-Shennawy, L.; Ramos, E.K.; Adorno-Cruz, V.; Schuster, E.J.; et al. ICAM1 initiates CTC cluster formation and trans-endothelial migration in lung metastasis of breast cancer. Nat. Commun. 2021, 12, 4867.
  36. Najmeh, S.; Cools-Lartigue, J.; Rayes, R.; Gowing, S.; Vourtzoumis, P.; Bourdeau, F.; Giannias, B.; Berube, J.; Rousseau, S.; Ferri, L.; et al. Neutrophil Extracellular Traps sequester circulating tumor cells via β1-integrin mediated interactions: NETs sequester CTCs via integrin β1. Int. J. Cancer 2017, 140.
  37. Canè, S.; Ugel, S.; Trovato, R.; Marigo, I.; De Sanctis, F.; Sartoris, S.; Bronte, V. The Endless Saga of Monocyte Diversity. Front. Immunol. 2019, 10.
  38. Shibuya, T.; Kamiyama, A.; Sawada, H.; Kikuchi, K.; Maruyama, M.; Sawado, R.; Ikeda, N.; Asano, K.; Kurotaki, D.; Tamura, T.; et al. Immunoregulatory Monocyte Subset Promotes Metastasis Associated With Therapeutic Intervention for Primary Tumor. Front. Immunol. 2021, 12, 663115.
  39. Jiang, Z.; Sun, H.; Yu, J.; Tian, W.; Song, Y. Targeting CD47 for cancer immunotherapy. J. Hematol. Oncol. 2021, 14, 180.
  40. Lin, Y.; Xu, J.; Lan, H. Tumor-associated macrophages in tumor metastasis: Biological roles and clinical therapeutic applications. J. Hematol. Oncol. 2019, 12, 76.
  41. Ge, Z.; Ding, S. The Crosstalk Between Tumor-Associated Macrophages (TAMs) and Tumor Cells and the Corresponding Targeted Therapy. Front. Oncol. 2020, 10.
  42. Chalfin, H.J.; Pramparo, T.; Mortazavi, A.; Niglio, S.A.; Schonhoft, J.D.; Jendrisak, A.; Chu, Y.L.; Richardson, R.; Krupa, R.; Anderson, A.K.L.; et al. Circulating Tumor Cell Subtypes and T-cell Populations as Prognostic Biomarkers to Combination Immunotherapy in Patients with Metastatic Genitourinary Cancer. Clin. Cancer Res. 2021, 27, 1391–1398.
  43. Kloten, V.; Lampignano, R.; Krahn, T.; Schlange, T. Circulating Tumor Cell PD-L1 Expression as Biomarker for Therapeutic Efficacy of Immune Checkpoint Inhibition in NSCLC. Cells 2019, 8, 809.
  44. Kotsakis, A.; Kallergi, G.; Aggouraki, D.; Lyristi, Z.; Koinis, F.; Lagoudaki, E.; Koutsopoulos, A.; Georgoulias, V.; Vetsika, E.K. CD8(+) PD-1(+) T-cells and PD-L1(+) circulating tumor cells in chemotherapy-naïve non-small cell lung cancer: Towards their clinical relevance? Adv. Med. Oncol. 2019, 11, 1758835919853193.
  45. Gruber, I.; Landenberger, N.; Staebler, A.; Hahn, M.; Wallwiener, D.; Fehm, T. Relationship between circulating tumor cells and peripheral T-cells in patients with primary breast cancer. Anticancer Res. 2013, 33, 2233–2238.
  46. Ye, L.; Zhang, F.; Li, H.; Yang, L.; Lv, T.; Gu, W.; Song, Y. Circulating Tumor Cells Were Associated with the Number of T Lymphocyte Subsets and NK Cells in Peripheral Blood in Advanced Non-Small-Cell Lung Cancer. Dis. Markers 2017, 2017, 5727815.
  47. Kondĕlková, K.; Vokurková, D.; Krejsek, J.; Borská, L.; Fiala, Z.; Ctirad, A. Regulatory T cells (TREG) and their roles in immune system with respect to immunopathological disorders. Acta Med. 2010, 53, 73–77.
  48. Chaudhary, B.; Elkord, E. Regulatory T Cells in the Tumor Microenvironment and Cancer Progression: Role and Therapeutic Targeting. Vaccines 2016, 4, 28.
  49. Taylor, A.; Verhagen, J.; Blaser, K.; Akdis, M.; Akdis, C.A. Mechanisms of immune suppression by interleukin-10 and transforming growth factor-beta: The role of T regulatory cells. Immunology 2006, 117, 433–442.
  50. Sun, Y.-F.; Wu, L.; Liu, S.-P.; Jiang, M.-M.; Hu, B.; Zhou, K.-Q.; Guo, W.; Xu, Y.; Zhong, Y.; Zhou, X.-R.; et al. Dissecting spatial heterogeneity and the immune-evasion mechanism of CTCs by single-cell RNA-seq in hepatocellular carcinoma. Nat. Commun. 2021, 12, 4091.
  51. Pantano, F.; Rossi, E.; Iuliani, M.; Facchinetti, A.; Simonetti, S.; Ribelli, G.; Zoccoli, A.; Vincenzi, B.; Tonini, G.; Zamarchi, R.; et al. Dynamic changes of Receptor activator of nuclear factor-κB expression in Circulating Tumor Cells during Denosumab predict treatment effectiveness in Metastatic Breast Cancer. Sci. Rep. 2020, 10, 1288.
  52. Mego, M.; Gao, H.; Cohen, E.N.; Anfossi, S.; Giordano, A.; Sanda, T.; Fouad, T.M.; De Giorgi, U.; Giuliano, M.; Woodward, W.A.; et al. Circulating Tumor Cells (CTC) Are Associated with Defects in Adaptive Immunity in Patients with Inflammatory Breast Cancer. J. Cancer 2016, 7, 1095–1104.
  53. Zhou, Y.; Wang, B.; Wu, J.; Zhang, C.; Zhou, Y.; Yang, X.; Zhou, J.; Guo, W.; Fan, J. Association of preoperative EpCAM Circulating Tumor Cells and peripheral Treg cell levels with early recurrence of hepatocellular carcinoma following radical hepatic resection. BMC Cancer 2016, 16, 506.
  54. Pitti, R.M.; Marsters, S.A.; Ruppert, S.; Donahue, C.J.; Moore, A.; Ashkenazi, A. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J. Biol. Chem. 1996, 271, 12687–12690.
  55. Takeda, K.; Hayakawa, Y.; Smyth, M.J.; Kayagaki, N.; Yamaguchi, N.; Kakuta, S.; Iwakura, Y.; Yagita, H.; Okumura, K. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat. Med. 2001, 7, 94–100.
  56. Twomey, J.D.; Zhang, B. Circulating Tumor Cells Develop Resistance to TRAIL-Induced Apoptosis Through Autophagic Removal of Death Receptor 5: Evidence from an In Vitro Model. Cancers 2019, 11.
  57. Brodbeck, T.; Nehmann, N.; Bethge, A.; Wedemann, G.; Schumacher, U. Perforin-dependent direct cytotoxicity in natural killer cells induces considerable knockdown of spontaneous lung metastases and computer modelling-proven tumor cell dormancy in a HT29 human colon cancer xenograft mouse model. Mol. Cancer 2014, 13, 244.
  58. Lo, H.C.; Xu, Z.; Kim, I.S.; Muscarella, A.; Liu, J.; Hein, S.; Wang, H.; Krupnick, A.; Neilson, J.; Paust, S.; et al. Circulating tumor cell clusters exhibit enhanced immune evasion from natural killer cells. J. Immunol. 2020, 204, 88.18.
  59. Lo, H.C.; Xu, Z.; Kim, I.S.; Pingel, B.; Aguirre, S.; Kodali, S.; Liu, J.; Zhang, W.; Muscarella, A.M.; Hein, S.M.; et al. Resistance to natural killer cell immunosurveillance confers a selective advantage to polyclonal metastasis. Nat. Cancer 2020, 1, 709–722.
  60. Perea Paizal, J.; Au, S.H.; Bakal, C. Squeezing through the microcirculation: Survival adaptations of circulating tumour cells to seed metastasis. Br. J. Cancer 2021, 124, 58–65.
  61. Au, S.H.; Storey, B.D.; Moore, J.C.; Tang, Q.; Chen, Y.-L.; Javaid, S.; Sarioglu, A.F.; Sullivan, R.; Madden, M.W.; O’Keefe, R.; et al. Clusters of circulating tumor cells traverse capillary-sized vessels. Proc. Natl. Acad. Sci. USA 2016, 113, 4947.
  62. Juan, S.J.P.; Garcia-Leon, M.J.; Rangel, L.; Goetz, J.G.; Chaffer, C.L. The Complexities of Metastasis. Cancers 2019, 11, 1575.
  63. Li, J.; King, M.R. Adhesion receptors as therapeutic targets for circulating tumor cells. Front. Oncol. 2012, 2, 79.
  64. Gil, C.D.; La, M.; Perretti, M.; Oliani, S.M. Interaction of human neutrophils with endothelial cells regulates the expression of endogenous proteins annexin 1, galectin-1 and galectin-3. Cell Biol. Int. 2006, 30, 338–344.
  65. Wu, Q.D.; Wang, J.H.; Condron, C.; Bouchier-Hayes, D.; Redmond, H.P. Human neutrophils facilitate tumor cell transendothelial migration. Am. J. Physiol. Cell Physiol. 2001, 280, C814–C822.
  66. Lozar, T.; Gersak, K.; Cemazar, M.; Kuhar, C.G.; Jesenko, T. The biology and clinical potential of circulating tumor cells. Radiol. Oncol. 2019, 53, 131–147.
  67. Wettschureck, N.; Strilic, B.; Offermanns, S. Passing the Vascular Barrier: Endothelial Signaling Processes Controlling Extravasation. Physiol. Rev. 2019, 99, 1467–1525.
  68. Kim, H.; Chung, H.; Kim, J.; Choi, D.-H.; Shin, Y.; Kang, Y.G.; Kim, B.-M.; Seo, S.-U.; Chung, S.; Seok, S.H. Macrophages-Triggered Sequential Remodeling of Endothelium-Interstitial Matrix to Form Pre-Metastatic Niche in Microfluidic Tumor Microenvironment. Adv. Sci. 2019, 6, 1900195.
  69. Shemanko, C.; Cong, Y.; Forsyth, A. What Is Breast in the Bone? Int. J. Mol. Sci. 2016, 17, 1764.
  70. Maurizi, A.; Rucci, N. The Osteoclast in Bone Metastasis: Player and Target. Cancers 2018, 10, 218.
  71. Schaller, J.; Agudo, J. Metastatic Colonization: Escaping Immune Surveillance. Cancers 2020, 12.
  72. Liu, Y.; Gu, Y.; Han, Y.; Zhang, Q.; Jiang, Z.; Zhang, X.; Huang, B.; Xu, X.; Zheng, J.; Cao, X. Tumor Exosomal RNAs Promote Lung Pre-metastatic Niche Formation by Activating Alveolar Epithelial TLR3 to Recruit Neutrophils. Cancer Cell 2016, 30, 243–256.
  73. Coffelt, S.B.; Kersten, K.; Doornebal, C.W.; Weiden, J.; Vrijland, K.; Hau, C.S.; Verstegen, N.J.M.; Ciampricotti, M.; Hawinkels, L.; Jonkers, J.; et al. IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis. Nature 2015, 522, 345–348.
  74. Pommier, A.; Anaparthy, N.; Memos, N.; Kelley, Z.L.; Gouronnec, A.; Yan, R.; Auffray, C.; Albrengues, J.; Egeblad, M.; Iacobuzio-Donahue, C.A.; et al. Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases. Science 2018, 360.
  75. Dhatchinamoorthy, K.; Colbert, J.D.; Rock, K.L. Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation. Front. Immunol. 2021, 12.
  76. Nakamura, K.; Smyth, M.J. Immunoediting of cancer metastasis by NK cells. Nat. Cancer 2020, 1, 670–671.
  77. Lee, C.-C.; Lin, J.-C.; Hwang, W.-L.; Kuo, Y.-J.; Chen, H.-K.; Tai, S.-K.; Lin, C.-C.; Yang, M.-H. Macrophage-secreted interleukin-35 regulates cancer cell plasticity to facilitate metastatic colonization. Nat. Commun. 2018, 9, 3763.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
ScholarVision Creations
Feedback