Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Myrofora Panagi
 + 2095 word(s) 2095 2021-04-27 08:53:25 |
2 update layout and reference
Rita Xu
 Meta information modification 2095 2021-05-08 08:53:50 |

Video Upload Options

We provide professional Video Production Services to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Panagi, M. Tumor Microenvironment in Cancer Metastasis. Encyclopedia. Available online: https://encyclopedia.pub/entry/9382 (accessed on 18 November 2024).
Panagi M. Tumor Microenvironment in Cancer Metastasis. Encyclopedia. Available at: https://encyclopedia.pub/entry/9382. Accessed November 18, 2024.
Panagi, Myrofora. "Tumor Microenvironment in Cancer Metastasis" Encyclopedia, https://encyclopedia.pub/entry/9382 (accessed November 18, 2024).
Panagi, M. (2021, May 07). Tumor Microenvironment in Cancer Metastasis. In Encyclopedia. https://encyclopedia.pub/entry/9382
Panagi, Myrofora. "Tumor Microenvironment in Cancer Metastasis." Encyclopedia. Web. 07 May, 2021.
Tumor Microenvironment in Cancer Metastasis
Edit
This entry is adapted from the peer-reviewed paper 10.3390/cancers13092053

Metastasis, the process by which cancer cells escape primary tumor site and colonize distant organs, is responsible for most cancer-related deaths. The tumor microenvironment (TME), comprises different cell types, including immune cells and cancer-associated fibroblasts, as well as structural elements, such as collagen and hyaluronan that constitute the extracellular matrix (ECM). 

tumor microenvironment immune system metastasis drug delivery cancer therapy

1. Introduction

Metastasis is responsible for more than 90% of cancer mortality; however, the underlying mechanisms driving this multistep process, ranging from local invasion at the primary site to the outgrowth of metastatic cells at the secondary sites, remain elusive. The communication between the neoplastic cells and the adjacent stromal cells begins at the earliest stages of tumor formation and continues during primary growth, local invasion, intravasation and establishment at the secondary site. While it was initially established that genetic aberrations are predominantly responsible for tumor initiation and progression [1], it has become clear during the last two decades that the tumor microenvironment (TME) plays an equally important role in modulating the aggressiveness, motility, dissemination, and colonization of cancer cells to distal organs [2]. The TME comprises the extracellular matrix (ECM) and basement membrane (BM), endothelial cells, adipose cells, tumor-infiltrating immune cells, cancer-associated fibroblasts (CAFs), neuroendocrine cells, pericytes, as well as a plethora of signalling molecules that regulate tumor progression. Cancer cells secrete growth factors and cytokines (including IL-6, IL-1β, TGF-β1, TGF-β2, FGF-2, and PDGF) that recruit and reprogram stromal cells, such as immune cells and fibroblasts, as well as enzymes that degrade and remodel the surrounding ECM and BM, such as matrix metalloproteinases (MMPs).

2. Roles of Cellular TME Components in Regulating the Metastatic Cascade

2.1. Role of Immune Cells in Modulating Cancer Metastasis

It is unambiguously accepted that immune cells exert pivotal effects in the properties of cancer cells at different stages of the invasion-metastasis cascade, either by infiltrating the tumor or by affecting the systemic environment [3]. During every step of this lethal process, cancer cells are being exposed to the immune system which attacks them to restrain their growth [4]. These anti-tumor effects are primarily mediated by CD8+ T cells as well as natural killer (NK) cells, which have been shown to restrict metastatic outgrowth of tumor cells, whereas their depletion enhances metastasis without affecting primary tumor growth [5][6][7]. However, during tumor evolution, cancer cells develop strategies not only to avoid immune surveillance but also to induce systemic responses by exploiting types of immune cells, such as myeloid cells, in order to enhance their metastatic efficiency [8].

The main type of myeloid cells implicated in regulating metastasis are macrophages, which are derived by hematopoietic stem cells (HSC) in the bone marrow and considered “professional” antigen presenting cells (APCs) [9]. They present foreign antigens to helper T cells and can prime naïve T cells. Macrophages are recruited to the tumor site via chemokines produced from cancer and stromal cells and are, thus, referred to as tumor-associated macrophages (TAMs). TAMs can act in two opposing functions depending on their polarization subtype: M1-type TAMs have pro-inflammatory and anti-tumoral properties and activate the immune system by releasing interferon (IFN)-γ and IL-12. On the other hand, M2-type TAMs are pro-tumorigenic, and exert immunosuppressive functions by producing IL-10, induce angiogenesis and stimulate tumor cells to release MMPs that favor cancer progression by disrupting the ECM and BM [10][11].

TAMs enable metastasis at various stages of the process, including activation of epithelial-to-mesenchymal transition (EMT), local invasion, and intravasation into the blood stream, transfer of cancer cells through the circulation, extravasation, and seeding at the secondary site, and finally promotion of survival and outgrowth of cancer cells at distant organs [12][13]. They achieve this by secreting numerous chemokines, inflammatory molecules, and growth factors that promote metastatic progression.

At the primary tumor site, TAMs help create a suitable microenvironment that allows tumor invasion [14]. The term “tumor microenvironment of metastasis” (TMEM) is proposed to describe the close arrangement of cancer cells, perivascular TAMs, and endothelial cells often located at sites of intravasation. Increased TMEM density in breast carcinoma patient samples positively correlates with increased risk of distant organ metastases [15]. During EMT, growth factors and cytokines, including TGF-β, Wnt, and EGF, can lead to the activation of an orchestrated transcriptional program during which tumor cells lose epithelial characteristics and gain mesenchymal features leading to increased capacity for invasion and metastasis [16][17]. Inflammation-induced EMT has also been reported and TAMs appear to play an important role in this transition. In hepatocellular carcinoma (HCC), TAMs are recruited by cancer cells by expressing glypican and secrete TGF-β, PDGF, VEGF, chemokine (C-C motif) ligand 2 (CCL2), and M-CSF [18][19]. In the tumor microenvironment, TAMs secrete many cytokines such as TGF-β and IL-6 that can induce EMT [20]. In pancreatic cancer, M2-polarized TAMs expressing Toll-like receptor 4 (TLR4) promoted EMT via TLR4/IL-10 signaling. Specifically, TAMs upregulated mesenchymal markers vimentin and snail, induced MMP-2 and MMP-9 proteolytic activity and diminished E-cadherin levels, leading to increased fibroblastic morphology, proliferation, and migration of pancreatic cancer cells [21]. TAMs exhibiting a CD68+HLA−DR+ surface marker phenotype can induce migration of HCC cells via the NF-κB/FAK pathway [22]. TAMs can further facilitate the invasiveness of cancer cells induced by phosphatase of regenerating liver (PRL-3), a marker of colorectal cancer (CRC) liver metastasis. CRC cells also produce PRL-3 and tumor necrosis factor-α (TNF-α) that increase the expression of intermediate-conductance Ca2+-activated potassium (KCNN4) channels in TAMs [23]; KCNN4 induce the secretion of IL-6 and IL-8 by TAMs and improve CRC cell invasiveness [24]. In addition, TAMs can release CCL18 chemokine that can stimulate angiogenesis and promote tumor progression in breast cancer [25]. In addition to their role in regulating migration and invasion of primary tumor cells, TAMs also mediate crucial functions on cancer cells disseminated at secondary tissues [26].

The term “metastasis-associated macrophages” (MAMs) is proposed to describe the role of macrophages that have infiltrated at the metastatic site. MAMs are essential for the extravasation of circulating tumor cells (CTCs) and their successful outgrowth at the secondary site, partly through VEGF expression [27]. The expression of CCL2 and the infiltration of the tumor site by macrophages have been correlated with metastatic disease in breast cancer [28][29]. MAMs that originate from inflammatory monocytes (IMs), are recruited to secondary sites along with monocytes expressing the CCR2 receptor. The stroma, as well as the tumor itself, are responsible for attracting these cells at the metastatic site by expressing CCL2 [30]. CCR2 activation following binding to CCL2 in MAMs, induces the secretion of the chemokine ligand CCL3 by macrophages at the metastatic site; this enables the retention of macrophages at the lung and increases the number of lung metastatic foci, whereas inhibition of CCR1, the receptor of CCL3, may have therapeutic implications in breast cancer lung metastasis [31]. Moreover, vascular cell adhesion molecule-1 (VCAM-1) expressed in breast cancer cells has been associated with lung metastasis relapse [32]. Following infiltration of breast cancer cells to the leukocyte-rich microenvironment of the lung, VCAM-1 provides a survival advantage by tethering MAMs to cancer cells via counter-receptor α4 integrins [32].

2.2. Role of Mesenchymal Stem Cells in Regulating Metastasis

Mesenchymal stem (or stromal) cells (MSCs) are multipotent stem cells that reside in many adult tissues, such as the bone marrow, adipose tissue, liver, lung, periosteum, muscle connective tissue, and spleen. They are important for generating and repairing skeletal tissues, such as cartilage and bone [33]. MSCs reside in most tumors and significantly influence the development and function of the TME. These cancer-associated MSC (CA-MSC) are reprogrammed by the tumor to exert pro-tumorigenic functions, such as enhancing EMT, promoting angiogenesis and metastasis.

Importantly, MSCs facilitate metastases by secreting exosomes which interact with cancer cells to affect their proliferation and migration [34][35]. They are the only type of cells that can mass produce exosomes [36]. Exosomes derived from MSCs are microvesicles (60–200 nm size) that have a phospholipid bilayer carrying proteins, lipids, miRNAs and mRNA [37]. They act in a paracrine fashion and can be detected in various body fluids [38]. In a breast cancer model, treatment with MSC-exosomes led to an enhanced migratory ability, through increased β-catenin levels and activation of WNT pathway target genes, Axin2 and Dkk1 [39]. Gastric cancer tissue-related mesenchymal stem cells (GC-MSCs), excrete exosomes carrying miRNAs that following delivery into gastric cancer cells can promote gastric cancer metastasis [40]. Particularly, the expression of miR-221 was significantly increased and correlated with enhanced local invasion, advanced tumor-node-metastasis stage, and lymphatic metastasis [41]. Overall, the presence of MSC-derived exosomes induced an EMT program and promoted migration and invasion of HGC-27 gastric cancer cells [42]. Bone marrow-derived mesenchymal stem cells (BM-MSCs), can also promote the migration of multiple myeloma cells by producing exosomes which selectively carry cytokines, such as chemotactic proteins MCP-1, MCP-2, MCP-3, 40 SDF-1, 41,42, and IGF-1 [43].

Contradicting to these reports, MSCs were also found to suppress metastatic tumor growth through their excreted exosomes carrying different strands of miRNAs. MSCs that interact with disseminated breast cancer cells in the bone marrow during the early stages of dissemination, promote cancer cell dormancy and enable an extended period of cycling quiescence in which cancer cells are maintained in G0/G1 phase of the cell cycle [44][45]. MSCs that produce exosomes with increased miR-23b and decreased MARCKS expression suppress cell cycle and promote dormancy of metastatic breast cancer cells [46][47].

2.3. Cancer-Associated Fibroblasts in Promoting Metastasis

CAFs constitute one of the most abundant stromal components in solid tumors. CAFs are distinguished from different cell subtypes based on the presence of several stromal markers, including integrin β1 (CD29), fibroblast activation protein (FAP), and α-smooth muscle actin (α-SMA) [48][49]. CAFs can be derived from different cell types of the TME: local fibroblasts that undergo mesenchymal–mesenchymal transition (MMT), epithelial cells via epithelial-to-mesenchymal transition (EMT), endothelial cells following endothelial-to-mesenchymal transition (endMT), bone marrow originated from hematopoietic stem cells or mesenchymal stem cells and adipocytes [50]. Cancer cells can activate fibroblasts in a three-step process: recruitment, transformation to CAFs, and maintenance in the TME. Following their activation, CAFs release signaling molecules to favor the survival of cancer cells and promote the recruitment and transformation of other cell types within the TME [51]. CAFs facilitate remodelling of the ECM by releasing collagen and fibronectin, producing MMPs, and increasing VEGF levels. This leads to the re-organization of the matrix, creating tracks which neoplastic cells exploit to directionally migrate, accompanied by CAFs [52][53][54][55][56][57].

The presence of a specific subset of CAFs in the microenvironment, CAF-S1, was recently shown to suppress the immune system by attracting and promoting the survival, differentiation, and activation of CD4+CD25+ T lymphocytes [49]. In addition, in women with primary tumors smaller than 2 cm without lymph node metastasis, the presence of CAF-S1 cells favors breast cancer metastasis to the bone via CDH11/osteoblast cadherin [58].

2.4. Endothelial Cells Attract Cancer Cells to the Metastatic Site

The lymphatic vessels that support the tumor at the secondary site are lined with loosely-connected lymphatic endothelial cells (LECs) that may also promote metastasis [59][60]. LECs recruit tumor cells by producing chemoattractants, such as CCL21 and SDF-1, which bind to CCR7 and CXCR4 receptors expressed in cancer cells, respectively [61]. Tumors developing at secondary organs produce factors that condition LECs to facilitate with cancer cell recruitment, extravasation, and outgrowth [62]. One example is the secretion of IL-6 by tumor cells that leads to STAT3 activation in LECs and subsequently high VEGF expression [62]. The expression of VEGF induced by tumor cells has been associated with the activation of HIF-1 in LECs, suggesting that tumor-secreted factors may support and direct lymphatic metastasis.

2.5. Components in the Blood Microenvironment That Facilitate Metastasis

During their dissemination throughout the body, circulating tumor cells (CTCs) encounter other cell types and factors in the peripheral blood that facilitate not only their survival but also their metastatic ability. These include various components, such as platelets, immune cells, cytokines, and circulating tumor microemboli (CTMs), which interact with CTCs and promote their survival [63]. Metastatic tumor cells can induce platelet adhesion and aggregation through the production of platelet activators such as ADP, thrombin, thromboxane, and von Willebrand factor [64]. Platelets enable the survival of cancer cells during their transit within the blood circulation and their colonization at the secondary site [65]. Platelets are a major source of lysophosphatidic acid (LPA), a natural lysophospholipid, which can bind to six different G-protein coupled receptors (GPCRs—LPA1-6 receptors) expressed on eukaryotic cells and activate multiple intracellular signaling pathways involved in cell survival, proliferation, differentiation, motility, cytoskeleton rearrangement and cytokine secretion [66]. Tumor cells induce platelet aggregation and production of LPA. Autotaxin (ATX), a lysophospholipase D also produced and released in platelet α-granules, is responsible for the basal concentration of LPA in blood. LPA interacts with different GPCRs found on cancer cells and promotes metastasis. The presence of certain cytokines in serum, including IL-17A, has also been correlated with increased number of CTCs and metastatic burden [67][68].

References

  1. Fearon, E.R.; Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 1990, 61, 759–767.
  2. Kurose, K.; Hoshaw-Woodard, S.; Adeyinka, A.; Lemeshow, S.; Watson, P.H.; Eng, C. Genetic model of multi-step breast carcino-genesis involving the epithelium and stroma: Clues to tumour-microenvironment interactions. Hum. Mol. Genet. 2001, 10, 1907–1913.
  3. Kitamura, T.; Qian, B.-Z.; Pollard, J.W. Immune cell promotion of metastasis. Nat. Rev. Immunol. 2015, 15, 73–86.
  4. Dunn, G.P.; Old, L.J.; Schreiber, R.D. The Immunobiology of Cancer Immunosurveillance and Immunoediting. Immunity 2004, 21, 137–148.
  5. Eyles, J.; Puaux, A.-L.; Wang, X.; Toh, B.; Prakash, C.; Hong, M.; Tan, T.G.; Zheng, L.; Ong, L.C.; Jin, Y.; et al. Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma. J. Clin. Investig. 2010, 120, 2030–2039.
  6. Paolino, M.; Choidas, A.; Wallner, S.; Pranjic, B.; Uribesalgo, I.; Loeser, S.; Jamieson, A.M.; Langdon, W.Y.; Ikeda, F.; Fededa, J.P.; et al. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nat. Cell Biol. 2014, 507, 508–512.
  7. Bidwell, B.N.; Slaney, C.Y.; Withana, N.P.; Forster, S.; Cao, Y.; Loi, S.; Andrews, D.; Mikeska, T.; Mangan, N.E.; Samarajiwa, S.A.; et al. Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape. Nat. Med. 2012, 18, 1224–1231.
  8. McAllister, S.S.; Weinberg, R.A. The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat. Cell Biol. 2014, 16, 717–727.
  9. Neophytou, C.M.; Pierides, C.; Christodoulou, M.I.; Costeas, P.; Kyriakou, T.C.; Papageorgis, P. The Role of Tumor-Associated My-eloid Cells in Modulating Cancer Therapy. Front. Oncol. 2020, 10, 899.
  10. Whipple, C.A. Tumor talk: Understanding the conversation between the tumor and its microenvironment. Cancer Cell Microenviron. 2015, 2, e773.
  11. Singh, S.; Mehta, N.; Lilan, J.; Budhthoki, M.B.; Chao, F.; Yong, L. Initiative action of tumor-associated macrophage during tumor metastasis. Biochim. Open 2017, 4, 8–18.
  12. Smith, H.A.; Kang, Y. The metastasis-promoting roles of tumor-associated immune cells. J. Mol. Med. 2013, 91, 411–429.
  13. Sanchez, L.R.; Borriello, L.; Entenberg, D.; Condeelis, J.S.; Oktay, M.H.; Karagiannis, G.S. The emerging roles of macrophages in cancer metastasis and response to chemotherapy. J. Leukoc. Biol. 2019, 106, 259–274.
  14. Wang, R.; Zhang, J.; Chen, S.; Lu, M.; Luo, X.; Yao, S.; Liu, S.; Qin, Y.; Chen, H. Tumor-associated macrophages provide a suitable microenvironment for non-small lung cancer invasion and progression. Lung Cancer 2011, 74, 188–196.
  15. Robinson, B.D.; Sica, G.L.; Liu, Y.-F.; Rohan, T.E.; Gertler, F.B.; Condeelis, J.S.; Jones, J.G. Tumor Microenvironment of Metastasis in Human Breast Carcinoma: A Potential Prognostic Marker Linked to Hematogenous Dissemination. Clin. Cancer Res. 2009, 15, 2433–2441.
  16. Thiery, J.P.; Acloque, H.; Huang, R.Y.; Nieto, M.A. Epithelial-Mesenchymal Transitions in Development and Disease. Cell 2009, 139, 871–890.
  17. Papageorgis, P. TGFbeta Signaling in Tumor Initiation, Epithelial-to-Mesenchymal Transition, and Metastasis. J. Oncol. 2015, 2015, 587193.
  18. Gupta, D.K.; Singh, N.; Sahu, D.K. TGF-beta Mediated Crosstalk Between Malignant Hepatocyte and Tumor Microenvironment in Hepatocellular Carcinoma. Cancer Growth Metastasis 2014, 7, 1–8.
  19. Zhu, X.-D.; Zhang, J.-B.; Zhuang, P.-Y.; Zhu, H.-G.; Zhang, W.; Xiong, Y.-Q.; Wu, W.-Z.; Wang, L.; Tang, Z.-Y.; Sun, H.-C. High Expression of Macrophage Colony-Stimulating Factor in Peritumoral Liver Tissue Is Associated with Poor Survival After Curative Resection of Hepatocellular Carcinoma. J. Clin. Oncol. 2008, 26, 2707–2716.
  20. Lewis, C.E.; Pollard, J.W. Distinct Role of Macrophages in Different Tumor Microenvironments. Cancer Res. 2006, 66, 605–612.
  21. Liu, C.Y.; Xu, J.Y.; Shi, X.Y.; Huang, W.; Ruan, T.Y.; Xie, P.; Ding, J.L. M2-polarized tumor-associated macrophages promoted epitheli-al-mesenchymal transition in pancreatic cancer cells, partially through TLR4/IL-10 signaling pathway. Lab. Investig. 2013, 93, 844–854.
  22. Wang, H.; Wang, X.; Li, X.; Fan, Y.; Li, G.; Guo, C.; Zhu, F.; Zhang, L.; Shi, Y. CD68(+)HLA-DR(+) M1-like macrophages promote motility of HCC cells via NF-kappaB/FAK pathway. Cancer Lett. 2014, 345, 91–99.
  23. Chu, Z.; Lai, W.; Chen, S.; Wu, H.; Guan, Y.; Liu, L.; Zeng, Y.; Zhao, H.; Jiang, J. PRL-3 promotes the proliferation of LoVo cells via the upregulation of KCNN4 channels. Oncol. Rep. 2011, 26, 909–917.
  24. Xu, H.; Lai, W.; Zhang, Y.; Liu, L.; Luo, X.; Zeng, Y.; Wu, H.; Lan, Q.; Chu, Z. Tumor-associated macrophage-derived IL-6 and IL-8 enhance invasive activity of LoVo cells induced by PRL-3 in a KCNN4 channel-dependent manner. BMC Cancer 2014, 14, 330.
  25. Lin, L.; Chen, Y.S.; Yao, Y.D.; Chen, J.Q.; Chen, J.N.; Huang, S.Y.; Zeng, Y.J.; Yao, H.R.; Zeng, S.H.; Fu, Y.S.; et al. CCL18 from tumor-associated macrophages promotes angio-genesis in breast cancer. Oncotarget 2015, 6, 34758–34773.
  26. Lin, Y.; Xu, J.; Lan, H. Tumor-associated macrophages in tumor metastasis: Biological roles and clinical therapeutic applica-tions. J. Hematol. Oncol. 2019, 12, 76.
  27. Qian, B.; Deng, Y.; Im, J.H.; Muschel, R.J.; Zou, Y.; Li, J.; Lang, R.A.; Pollard, J.W. A Distinct Macrophage Population Mediates Metastatic Breast Cancer Cell Extravasation, Establishment and Growth. PLoS ONE 2009, 4, e6562.
  28. Ueno, T.; Toi, M.; Saji, H.; Muta, M.; Bando, H.; Kuroi, K.; Koike, M.; Inadera, H.; Matsushima, K. Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer. Clin. Cancer Res. 2000, 6, 3282–3289.
  29. Saji, H.; Koike, M.; Yamori, T.; Saji, S.; Seiki, M.; Matsushima, K.; Toi, M. Significant correlation of monocyte chemoattractant protein-1 expression with neovascularization and progression of breast carcinoma. Cancer 2001, 92, 1085–1091.
  30. Qian, B.-Z.; Li, J.; Zhang, H.; Kitamura, T.; Zhang, J.; Campion, L.R.; Kaiser, E.A.; Snyder, L.A.; Pollard, J.W. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 2011, 475, 222–225.
  31. Kitamura, T.; Qian, B.-Z.; Soong, D.; Cassetta, L.; Noy, R.; Sugano, G.; Kato, Y.; Li, J.; Pollard, J.W. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J. Exp. Med. 2015, 212, 1043–1059.
  32. Chen, Q.; Zhang, X.H.-F.; Massagué, J. Macrophage Binding to Receptor VCAM-1 Transmits Survival Signals in Breast Cancer Cells that Invade the Lungs. Cancer Cell 2011, 20, 538–549.
  33. Ding, D.-C.; Shyu, W.-C.; Lin, S.-Z. Mesenchymal Stem Cells. Cell Transplant. 2011, 20, 5–14.
  34. Zhou, J.; Tan, X.; Tan, Y.; Li, Q.; Ma, J.; Wang, G. Mesenchymal Stem Cell Derived Exosomes in Cancer Progression, Metastasis and Drug Delivery: A Comprehensive Review. J. Cancer 2018, 9, 3129–3137.
  35. Atiya, H.; Frisbie, L.; Pressimone, C.; Coffman, L. Mesenchymal Stem Cells in the Tumor Microenvironment. Adv. Exp. Med. Biol. 2020, 1234, 31–42.
  36. Yeo, R.W.Y.; Lai, R.C.; Zhang, B.; Tan, S.S.; Yin, Y.; Teh, B.J.; Lim, S.K. Mesenchymal stem cell: An efficient mass producer of exosomes for drug delivery. Adv. Drug Deliv. Rev. 2013, 65, 336–341.
  37. Simpson, R.J.; Lim, J.W.; Moritz, R.L.; Mathivanan, S. Exosomes: Proteomic insights and diagnostic potential. Expert Rev. Proteom. 2009, 6, 267–283.
  38. Mathivanan, S.; Fahner, C.J.; Reid, G.E.; Simpson, R.J. ExoCarta 2012: Database of exosomal proteins, RNA and lipids. Nucleic Acids Res. 2011, 40, D1241–D1244.
  39. Lin, R.; Wang, S.; Zhao, R.C. Exosomes from human adipose-derived mesenchymal stem cells promote migration through Wnt signaling pathway in a breast cancer cell model. Mol. Cell. Biochem. 2013, 383, 13–20.
  40. Wang, M.; Zhao, C.; Shi, H.; Zhang, B.; Zhang, L.; Zhang, X.; Wang, S.; Wu, X.; Yang, T.; Huang, F.; et al. Deregulated microRNAs in gastric cancer tissue-derived mesen-chymal stem cells: Novel biomarkers and a mechanism for gastric cancer. Br. J. Cancer. 2014, 110, 1199–1210.
  41. Liu, K.; Li, G.; Fan, C.; Diao, Y.; Wu, B.; Li, J. Increased Expression of MicroRNA-221 in gastric cancer and its clinical significance. J. Int. Med. Res. 2012, 40, 467–474.
  42. Gu, H.; Ji, R.; Zhang, X.; Wang, M.; Zhu, W.; Qian, H.; Chen, Y.; Jiang, P.; Xu, W. Exosomes derived from human mesenchymal stem cells promote gastric cancer cell growth and migration via the activation of the Akt pathway. Mol. Med. Rep. 2016, 14, 3452–3458.
  43. Wang, J.; Hendrix, A.; Hernot, S.; Lemaire, M.; De Bruyne, E.; Van Valckenborgh, E.; Lahoutte, T.; De Wever, O.; Vanderkerken, K.; Menu, E.; et al. Bone marrow stromal cell-derived ex-osomes as communicators in drug resistance in multiple myeloma cells. Blood 2014, 124, 555–566.
  44. Casson, J.; Davies, O.G.; Smith, C.-A.; Dalby, M.J.; Berry, C.C. Mesenchymal stem cell-derived extracellular vesicles may promote breast cancer cell dormancy. J. Tissue Eng. 2018, 9.
  45. Neophytou, C.M.; Kyriakou, T.-C.; Papageorgis, P. Mechanisms of Metastatic Tumor Dormancy and Implications for Cancer Therapy. Int. J. Mol. Sci. 2019, 20, 6158.
  46. Ono, M.; Kosaka, N.; Tominaga, N.; Yoshioka, Y.; Takeshita, F.; Takahashi, R.-U.; Yoshida, M.; Tsuda, H.; Tamura, K.; Ochiya, T. Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells. Sci. Signal. 2014, 7, ra63.
  47. Bliss, S.A.; Sinha, G.; Sandiford, O.A.; Williams, L.M.; Engelberth, D.J.; Guiro, K.; Isenalumhe, L.L.; Greco, S.J.; Ayer, S.; Bryan, M.; et al. Mesenchymal stem cell–derived exosomes stimulate cycling quiescence and early breast cancer dormancy in bone marrow. Cancer Res. 2016, 76, 5832–5844.
  48. Puré, E.; Blomberg, R. Pro-tumorigenic roles of fibroblast activation protein in cancer: Back to the basics. Oncogene 2018, 37, 4343–4357.
  49. Costa, A.; Kieffer, Y.; Scholer-Dahirel, A.; Pelon, F.; Bourachot, B.; Cardon, M.; Sirven, P.; Magagna, I.; Fuhrmann, L.; Bernard, C.; et al. Fibroblast Heterogeneity and Immunosup-pressive Environment in Human Breast Cancer. Cancer Cell 2018, 33, 463–479.e10.
  50. Shiga, K.; Hara, M.; Nagasaki, T.; Sato, T.; Takahashi, H.; Takeyama, H. Cancer-Associated Fibroblasts: Their Characteristics and Their Roles in Tumor Growth. Cancers 2015, 7, 2443–2458.
  51. Heneberg, P. Paracrine tumor signaling induces transdifferentiation of surrounding fibroblasts. Crit. Rev. Oncol. 2016, 97, 303–311.
  52. Räsänen, K.; Vaheri, A. Activation of fibroblasts in cancer stroma. Exp. Cell Res. 2010, 316, 2713–2722.
  53. Gaggioli, C.; Hooper, S.; Hidalgo-Carcedo, C.; Grosse, R.; Marshall, J.F.; Harrington, K.; Sahai, E. Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat. Cell Biol. 2007, 9, 1392–1400.
  54. Eck, S.M.; Cote, A.L.; Winkelman, W.D.; Brinckerhoff, C.E. CXCR4 and matrix metalloproteinase-1 are elevated in breast carcino-ma-associated fibroblasts and in normal mammary fibroblasts exposed to factors secreted by breast cancer cells. Mol. Cancer Res. 2009, 7, 1033–1044.
  55. Murphy, G.; Nagase, H. Progress in matrix metalloproteinase research. Mol. Asp. Med. 2008, 29, 290–308.
  56. Gonzalez-Avila, G.; Sommer, B.; Mendoza-Posada, D.A.; Ramos, C.; Garcia-Hernandez, A.A.; Falfan-Valencia, R. Matrix metallo-proteinases participation in the metastatic process and their diagnostic and therapeutic applications in cancer. Crit. Rev. Oncol. Hematol. 2019, 137, 57–83.
  57. Erdogan, B.; Ao, M.; White, L.M.; Means, A.L.; Brewer, B.M.; Yang, L.; Washington, M.K.; Shi, C.; Franco, O.E.; Weaver, A.M.; et al. Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin. J. Cell Biol. 2017, 216, 3799–3816.
  58. Bonneau, C.; Eliès, A.; Kieffer, Y.; Bourachot, B.; Ladoire, S.; Pelon, F.; Hequet, D.; Guinebretière, J.-M.; Blanchet, C.; Vincent-Salomon, A.; et al. A subset of activated fibroblasts is associated with distant relapse in early luminal breast cancer. Breast Cancer Res. 2020, 22, 1–22.
  59. Rankin, E.B.; Giaccia, A.J. Hypoxic control of metastasis. Science 2016, 352, 175–180.
  60. Smolarczyk, R.; Czapla, J.; Jarosz-Biej, M.; Czerwinski, K.; Cichoń, T. Vascular disrupting agents in cancer therapy. Eur. J. Pharmacol. 2021, 891, 173692.
  61. Albrecht, I.; Christofori, G. Molecular mechanisms of lymphangiogenesis in development and cancer. Int. J. Dev. Biol. 2011, 55, 483–494.
  62. Lee, E.; Fertig, E.J.; Jin, K.; Sukumar, S.; Pandey, N.B.; Popel, A.S. Breast cancer cells condition lymphatic endothelial cells within pre-metastatic niches to promote metastasis. Nat. Commun. 2014, 5, 1–16.
  63. Wang, W.-C.; Zhang, X.-F.; Peng, J.; Li, X.-F.; Wang, A.-L.; Bie, Y.-Q.; Shi, L.-H.; Lin, M.-B. Survival Mechanisms and Influence Factors of Circulating Tumor Cells. BioMed Res. Int. 2018, 2018, 1–9.
  64. Camerer, E.; Qazi, A.A.; Duong, D.N.; Cornelissen, I.; Advincula, R.; Coughlin, S.R. Platelets, protease-activated receptors, and fi-brinogen in hematogenous metastasis. Blood 2004, 104, 397–401.
  65. Gay, L.J.; Felding-Habermann, B. Contribution of platelets to tumour metastasis. Nat. Rev. Cancer 2011, 11, 123–134.
  66. Mutoh, T.; Rivera, R.; Chun, J. Insights into the pharmacological relevance of lysophospholipid receptors. Br. J. Pharmacol. 2012, 165, 829–844.
  67. Tseng, J.Y.; Yang, C.Y.; Liang, S.C.; Liu, R.S.; Yang, S.H.; Lin, J.K.; Chen, Y.M.; Wu, Y.C.; Jiang, J.K.; Lin, C.H. Interleukin-17A modulates circulating tumor cells in tumor draining vein of colorectal cancers and affects metastases. Clin. Cancer Res. 2014, 20, 2885–2897.
  68. Leblanc, R.; Houssin, A.; Peyruchaud, O. Platelets, autotaxin and lysophosphatidic acid signalling: Win-win factors for cancer metastasis. Br. J. Pharmacol. 2018, 175, 3100–3110.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Oncology
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Myrofora Panagi
View Times: 663
Revisions: 2 times (View History)
Update Date: 08 May 2021
Table of Contents
    1000/1000
    Hot Most Recent
    ScholarVision Creations
    Feedback