This excellent question is essentially about two related subprocesses that constitute the "early game" of the tumor cell circulation and early metastatic process, namely:
(1) INTRAVASATION which is the endothelial transmigration of tumor cells into blood vessels in the vasculature, and
(2) HEMATOGENOUS SURVIVAL (tumor cell survival in the circulatory system, once the tumor cell arrives there via intravasation),
which together are called HEMATOGENOUS DISSEMINATION.
I will give, below, a reasonably brief sketch of these subprocesses here (distilled from a lengthier 40+ page review of the metastatic process and cascade I recently completed [Kaniklidis, C. The Early Game of Metastasis: Tumor Cell Circulation via Intravasation and Hematogenous Survival. (pending)].
The Metastatic Process: Brief summary
The multi-step process of metastasis is a complex and coordinated choreography encompassing:
(1) local infiltration of tumor cells into the surrounding/adjacent tissue (tumor cell penetration through the ECM / the basement membrane),
(2) intravasation (endothelial transmigration of tumor cells into vessels),
(3) hematogenous survival and translocation, that is, the tumor cell survival in the circulatory system and its translocation through the bloodstream to microvessels of distant tissues
(4) extravasation (exit from bloodstream, and
(5) adaption to the foreign microenvironment of distant site tissue and subsequent colonization (cell proliferation and the formation of a macroscopic secondary tumor) in competent organs.
Subprocesses (2) and (3) together, that is, the combination of intravasation + hematogenous survival constitute collectively what is known as hematogenous dissemination.
Intravasation
Tumor cells intravasation, which is the endothelial transmigration of cancer cells into vessels, involves two different types of motility: tumor cells can intravasate the blood, or the lymph vasculature, although dissemination via the hematogenous route seems to represents the major mechanism for dispersal of metastatic carcinoma cells [1], and for both routes, the process is mechanistically via interaction of tumor cells with the vascular endothelium. Note however that although the primary main route of the metastatic spread has generally until recently been the blood / circulation system, mounting evidence suggests that the lymphatic system is also a key player in cancer cell dissemination. But as to the central matter of endothelial transmigration of tumor cells, there remains indeterminacy and continued debate on the question of active versus passive dissemination, that is, as to whether (1) tumor cells actively migrate through blood and lymph vasculature as a response to phenomenon like growth factor gradients, or (2) do so passively by "crawling" into the vasculature even in the absence an active cell migration machinery, leading to a neatly phrased article title from Lance Munn and colleagues, namely "Do cancer cells crawl into vessels, or are they pushed?" [2].
There are a number of molecular phenomena that facilitate endothelial transmigration, that is, the crossing by tumor cells of the pericyte and endothelial cell barriers that constitute the microvessel walls:
(1) Twist:
Jing Yang et al. have shown in a murine breast cancer model that the transcription factor, Twist, appears to allow the step of intravasation and hence functions as an EMT-inducing transcription factor and thus a key regulator of metastasis [3], both augmenting EMT (epithelial-to-mesenchymal) transitions and promoting the rate of hematogenous intravasation.
(2) Chemoattractive Gradients and the Role of EGF / CSF-1:
In addition, a second mechanism is at play, as documented in the breast cancer context, that involves what is called chemoattractive gradients, confirmed by direct visualization using multiphoton microscopy by researchers at the Albert Einstein College of Medicine [4,5]. These direct observations demonstrated how perivascular macrophages in mammary tumors are critically involved in intravasation and hematogenous survival, and that these perivascular macrophages synergistically induce tumor cell intravasation even in the absence of local angiogenesis. These perivascular macrophages are recruited by the tumor cells to the injured site (Condeelis), inducing intravasation into the blood system via chemoattractive gradients generated by these same perivascular macrophages, with crosstalk and collaboration between the tumor microenvironment and the tumor cells at the intravasation site is enabled thorough a positive-feedback loop constituted by the reciprocal secretion of epidermal growth factor (EGF) created by the macrophages and colony stimulating factor-1 (CSF-1) by the tumor cells, jointly augmenting chemotaxis and the intravasation process, with EGF promoting tumor cell migration into the hematogenous vasculature through interaction with the EGF receptor, and CSF-1 expressed on the tumor cells functioning as a potent chemoattractant for CSF-1 receptor positive macrophages [6,7].
(3) Transforming Growth Factor-beta (TGF-beta):
In mammary carcinoma, the cytokine TGF-beta (transforming growth factor-beta) enhances intravasation via increased penetration of microvessel walls, suggesting that transient TGF-beta signalling is critical for blood-born metastasis [8].
(4) VEGF and Neoangiogenesis:
Via VEGF and neoangiogenesis, tumor cells stimulate formation of new blood vessels within the local microenvironment, with the neovasculature created by tumor cells being prone to leakiness, and ultimately facilitate intravasation [9].
Hematogenous Survival: Survival in Vasculature
But after successful invasion of the hematogenous vasculature, tumor cells must survive a perilous microenvironment of challenging hurdles that include hemodynamic shear forces turbulence, surveillance from and attack by immune cells especially natural killer (NK) cells, and lack of substratum, and entrapment-by-size in early-encountered capillary beds, which occurs usually even in the first capillary bed encountered by the tumor cells consequent to the fact that the diameter of most tumor cells is too large for passage through small capillaries [10].
A main defense for hematogenous survival used by tumor cells is using platelets as a shield, by binding coagulation factors on the platelets, forming an embolus aggregate that protects the tumor cells from immune-cell-mediated lysis / destruction, as well as decreases the level and impact of the circulation system's hemodynamic shear forces and turbulence, to enhance survival [11-14].
In addition, tumor cells are physically shielded from the stress of blood flow, shear forces and turbulence, as well as from lysis by NK cells by two related processes:
(1) activation of the coagulation cascade and
(2) formation of platelet-rich thrombi around tumor cells in the vasculature [15-18]. The process,
in essence, is that tumor cell tissue factor triggers thrombin formation that initiates both coagulation and platelet activation, which in turn enhance metastatic spread. And Fibrin can be bound by integrins on tumor cells and on activated platelets, triggering the formation of tumor-cell–fibrin–platelet aggregates. These large aggregates and emboli then have the strength and resiliency to survive hematogenous shear forces and turbulence [17,19-22]
And it appears that the normal anti-tumor reactivity of NK immune cells can be subverted by a platelet-derived coating (called MHC Class I) which disguises the tumor cell with a pseudo-normal phenotype, exempting it from immune response and attack. [23,24].
Methodology of this Review
A search of the PUBMED, Cochrane Register of Controlled Trials, MEDLINE, EMBASE, AMED, CINAHL, PsycINFO, (WoS) Web of Science, BIOSIS, LILACS and Scirus databases was conducted without language or date restrictions, and updated again current as of date of publication, with systematic reviews and meta-analyses extracted separately. Search was expanded in parallel to include just-in-time (JIT) medical feed sources as returned from Terkko (provided by the National Library of Health Sciences - Terkko at the University of Helsinki). A further "broad-spectrum" science search using Scirus (410+ million entry database) was then deployed for resources not otherwise included. Unpublished studies were located via contextual search, and relevant dissertations were located via NTLTD (Networked Digital Library of Theses and Dissertations) and OpenThesis. Sources in languages foreign to this reviewer were translated by language translation software.
References
1. Gupta GP, Massagué J. Cancer metastasis: building a framework. Cell 2006 Nov 17; 127(4):679-95.
2. Bockhorn M, Jain RK, Munn LL. Active versus passive mechanisms in metastasis: do cancer cells crawl into vessels, or are they pushed? Lancet Oncol 2007; 8(5):444-8.
3. Yang J, Mani SA, Donaher JL, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004 Jun 25; 117(7):927-39.
4. Condeelis J, Segall JE. “Intravital imaging of cell movement in tumours,” Nat Rev Cancer. 2003 Dec;3(12):921-30;
5. Wyckoff JB, Wang Y, Lin EY, et al. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res 2007 Mar 15; 67(6):2649-56.
6. Wyckoff J, Wang W, Lin EY, et al. A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res 2004 Oct 1; 64(19):7022-9.
7. Goswami S, Sahai E, Wyckoff JB, et al. Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop. Cancer Res. 2005 Jun 15;65(12):5278-83.
8. Giampieri S, Manning C, Hooper S, Jones L, Hill CS, Sahai E. Localized and reversible TGFbeta signalling switches breast cancer cells from cohesive to single cell motility. Nat Cell Biol. 2009 Nov;11(11):1287-96.
9. Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 2011; 10(6):417-27.
10. Steeg PS. Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 2006; 12(8):895-904.
11. Palumbo JS. Mechanisms linking tumor cell-associated procoagulant function to tumor dissemination. Semin Thromb Hemost 2008; 34(2):154-60.
12. Im JH, Fu W, Wang H, et al. Coagulation facilitates tumor cell spreading in the pulmonary vasculature during early metastatic colony formation. Cancer Res 2004; 64(23): 8613–8619.
13. Palumbo JS, Talmage KE, Massari JV, et al. Tumor cell-associated tissue factor and circulating hemostatic factors cooperate to increase metastatic potential through natural killer cell-dependent and -independent mechanisms. Blood 2007 110(1):133–141.
14. Khamis ZI, Sahab ZJ, Sang QX. Active roles of tumor stroma in breast cancer metastasis. Int J Breast Cancer 2012; 2012:574025.
15. Palumbo JS, Talmage KE, Massari JV, et al. Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. Blood 2005; 105:178–85.
16. [Erpenbeck L, Schon MP. Deadly allies: the fatal interplay between platelets and metastasizing cancer cells. Blood 2010; 115:3427–36.
17. Gay LJ, Felding-Habermann B. Contribution of platelets to tumour metastasis. Nat Rev Cancer 2011; 11:123–34.
18. Degen JL , Palumbo JS . Hemostatic factors, innate immunity and malignancy. Thromb Res 2012; 129 Suppl 1:S1–5.
19. Liu Y, Jiang P, Capkova K, et al. Tissue factor activated coagulation cascade in the tumor microenvironment is critical for tumor progression and an effective target for therapy. Cancer Res 2011; 71:6492–502.]
20. Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell 2011; 20:576–90.
21. Camerer E, Qazi AA, Duong DN, Cornelissen I, Advincula R, Coughlin SR. Platelets, protease-activated receptors, and fibrinogen in hematogenous metastasis. Blood 2004;104:397–401.
22. [Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell 2011 Oct 14; 147(2):275-92.
23. Placke T, Oergel M, Schaller M, J, et al. Platelet-derived MHC Class I confers a pseudo-normal phenotype to cancer cells that subverts the anti-tumor reactivity of natural killer immune cells. Cancer Res 2012; 72:440–8.
24. Nieswandt B, Hafner M, Echtenacher B, Mannel DN. Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res 1999 59:1295–1300.
Dear Christer
Generally by passive shedding. It is imaginable that in case of an aggressive tumor the directed migration mechanism exits. It is known that the patient has many metastases, however the initial tumor is very small.
This is my opinion and yours?
with best wishes
Eva
Well all the cells in an overt primary malignancy are neither capable of invasion nor metastasis. There is always a continued evolution through clonal expansion and hetergenity, which leads to acquisition of new traits and in this process some of the clones acquire metastatic potential by inhibition, down-regulation or deletion of metastatic suppressor genes such nm23-H1and 2, Drg1. BRMS1, KiSS1, MAPK4, CD44,KAI1 etc.In other words there are pre-existing metastatic sub-clones that are exclusively capable of metastasis as thought of lately. Thus there seems to be a possibility of directed migration by some cross-talk mode that leads to intravasation and circulation of cancer cells. The corroborative evidence that some of the cancers with the mutations of the said genes readily metastasize also leads us us to believe this. In addition, why certain cancers hardly metastasize irrespective of their size, grade and invasability e. g. basal cell tumor also suggests lack of directed migration in such cases. Of course, EMT is a stepping stone for migration of tumor cells from the primary site.
@Naresh: Does this necessarily mean that all CTCs are metastasis originating from a primary tumor site ?
No, Dear Hartmann, there can be CTCs from secondary sites, which may lead to a secondary metastasis. But presumably all the cells entering from metastastic sites too may have inactivation of metastatic suppressor genes. Let us wait till further information gathers.
Hi
The precondition for a tumour metastasis are the followings: (1) The viability of the shed cells, (2) The metastatic potential of these cells, (3) The proliferative potential of the cells. All these factors are important and necessary....
We must not forget also the tumour-microenvironment and the immunocompetent cells. They could be decisive in the development of the metastasis (metastases).
A nice weekend
Best
Eva
Dear Christer
Immune response should also contribute to tumor metastasis. Actually, there are many studies about the role of M2 macrophages in tumor development. The paper entitled “Immunity, Inflammation and Cancer” (Cell. 2010 March 19; 140(6): 883–899) is an interesting review about the topic.
My bes regards
Dear Christopher
In the end the immune-defense-system decides whether the CTCs lead to metastases or not.
This immune-defense-system consists of specific immunocompetent cells + specific immunofactors. This "army" is able to eliminate the CTCs. All clinical practitioners can confirm this fact.
with best regards
Eva
Yes, of course only 0.001% of the cells that detach from primary mass are able to form metastasis, also known as metastatic inefficiency from tumor angle. In fact, majority of the cancer cells are destroyed en-route to metastatic target.
Where does that number "0.001% of the cells that detach from primary mass are able to form metastasi" come from? Is there a good reference that has proven this (and for what tumor type?) or is this an assumtion?
Dear Becker, Please find the links below for more information
http://cancerres.aacrjournals.org/content/52/6/1399
link.springer.com/content/pdf/10.1007%2F978-1-84628-947-7_2.pdf
Regards
I agree with Christopher's views. Just to add layman's definitions to the current topic. Invasion means detachment of cancer cells from their site of oigin. It is achieved by the breakdown of basement membrane (in the case of tumors of epithelial origin) and requires Matrix metalloproteinases (MMPs). Metastasis is transport of invasive tumor cells to new sites within the patients body. Both of these processes requires genetic, epigenetic and immunological inputs.
This excellent question is essentially about two related subprocesses that constitute the "early game" of the tumor cell circulation and early metastatic process, namely:
(1) INTRAVASATION which is the endothelial transmigration of tumor cells into blood vessels in the vasculature, and
(2) HEMATOGENOUS SURVIVAL (tumor cell survival in the circulatory system, once the tumor cell arrives there via intravasation),
which together are called HEMATOGENOUS DISSEMINATION.
I will give, below, a reasonably brief sketch of these subprocesses here (distilled from a lengthier 40+ page review of the metastatic process and cascade I recently completed [Kaniklidis, C. The Early Game of Metastasis: Tumor Cell Circulation via Intravasation and Hematogenous Survival. (pending)].
The Metastatic Process: Brief summary
The multi-step process of metastasis is a complex and coordinated choreography encompassing:
(1) local infiltration of tumor cells into the surrounding/adjacent tissue (tumor cell penetration through the ECM / the basement membrane),
(2) intravasation (endothelial transmigration of tumor cells into vessels),
(3) hematogenous survival and translocation, that is, the tumor cell survival in the circulatory system and its translocation through the bloodstream to microvessels of distant tissues
(4) extravasation (exit from bloodstream, and
(5) adaption to the foreign microenvironment of distant site tissue and subsequent colonization (cell proliferation and the formation of a macroscopic secondary tumor) in competent organs.
Subprocesses (2) and (3) together, that is, the combination of intravasation + hematogenous survival constitute collectively what is known as hematogenous dissemination.
Intravasation
Tumor cells intravasation, which is the endothelial transmigration of cancer cells into vessels, involves two different types of motility: tumor cells can intravasate the blood, or the lymph vasculature, although dissemination via the hematogenous route seems to represents the major mechanism for dispersal of metastatic carcinoma cells [1], and for both routes, the process is mechanistically via interaction of tumor cells with the vascular endothelium. Note however that although the primary main route of the metastatic spread has generally until recently been the blood / circulation system, mounting evidence suggests that the lymphatic system is also a key player in cancer cell dissemination. But as to the central matter of endothelial transmigration of tumor cells, there remains indeterminacy and continued debate on the question of active versus passive dissemination, that is, as to whether (1) tumor cells actively migrate through blood and lymph vasculature as a response to phenomenon like growth factor gradients, or (2) do so passively by "crawling" into the vasculature even in the absence an active cell migration machinery, leading to a neatly phrased article title from Lance Munn and colleagues, namely "Do cancer cells crawl into vessels, or are they pushed?" [2].
There are a number of molecular phenomena that facilitate endothelial transmigration, that is, the crossing by tumor cells of the pericyte and endothelial cell barriers that constitute the microvessel walls:
(1) Twist:
Jing Yang et al. have shown in a murine breast cancer model that the transcription factor, Twist, appears to allow the step of intravasation and hence functions as an EMT-inducing transcription factor and thus a key regulator of metastasis [3], both augmenting EMT (epithelial-to-mesenchymal) transitions and promoting the rate of hematogenous intravasation.
(2) Chemoattractive Gradients and the Role of EGF / CSF-1:
In addition, a second mechanism is at play, as documented in the breast cancer context, that involves what is called chemoattractive gradients, confirmed by direct visualization using multiphoton microscopy by researchers at the Albert Einstein College of Medicine [4,5]. These direct observations demonstrated how perivascular macrophages in mammary tumors are critically involved in intravasation and hematogenous survival, and that these perivascular macrophages synergistically induce tumor cell intravasation even in the absence of local angiogenesis. These perivascular macrophages are recruited by the tumor cells to the injured site (Condeelis), inducing intravasation into the blood system via chemoattractive gradients generated by these same perivascular macrophages, with crosstalk and collaboration between the tumor microenvironment and the tumor cells at the intravasation site is enabled thorough a positive-feedback loop constituted by the reciprocal secretion of epidermal growth factor (EGF) created by the macrophages and colony stimulating factor-1 (CSF-1) by the tumor cells, jointly augmenting chemotaxis and the intravasation process, with EGF promoting tumor cell migration into the hematogenous vasculature through interaction with the EGF receptor, and CSF-1 expressed on the tumor cells functioning as a potent chemoattractant for CSF-1 receptor positive macrophages [6,7].
(3) Transforming Growth Factor-beta (TGF-beta):
In mammary carcinoma, the cytokine TGF-beta (transforming growth factor-beta) enhances intravasation via increased penetration of microvessel walls, suggesting that transient TGF-beta signalling is critical for blood-born metastasis [8].
(4) VEGF and Neoangiogenesis:
Via VEGF and neoangiogenesis, tumor cells stimulate formation of new blood vessels within the local microenvironment, with the neovasculature created by tumor cells being prone to leakiness, and ultimately facilitate intravasation [9].
Hematogenous Survival: Survival in Vasculature
But after successful invasion of the hematogenous vasculature, tumor cells must survive a perilous microenvironment of challenging hurdles that include hemodynamic shear forces turbulence, surveillance from and attack by immune cells especially natural killer (NK) cells, and lack of substratum, and entrapment-by-size in early-encountered capillary beds, which occurs usually even in the first capillary bed encountered by the tumor cells consequent to the fact that the diameter of most tumor cells is too large for passage through small capillaries [10].
A main defense for hematogenous survival used by tumor cells is using platelets as a shield, by binding coagulation factors on the platelets, forming an embolus aggregate that protects the tumor cells from immune-cell-mediated lysis / destruction, as well as decreases the level and impact of the circulation system's hemodynamic shear forces and turbulence, to enhance survival [11-14].
In addition, tumor cells are physically shielded from the stress of blood flow, shear forces and turbulence, as well as from lysis by NK cells by two related processes:
(1) activation of the coagulation cascade and
(2) formation of platelet-rich thrombi around tumor cells in the vasculature [15-18]. The process,
in essence, is that tumor cell tissue factor triggers thrombin formation that initiates both coagulation and platelet activation, which in turn enhance metastatic spread. And Fibrin can be bound by integrins on tumor cells and on activated platelets, triggering the formation of tumor-cell–fibrin–platelet aggregates. These large aggregates and emboli then have the strength and resiliency to survive hematogenous shear forces and turbulence [17,19-22]
And it appears that the normal anti-tumor reactivity of NK immune cells can be subverted by a platelet-derived coating (called MHC Class I) which disguises the tumor cell with a pseudo-normal phenotype, exempting it from immune response and attack. [23,24].
Methodology of this Review
A search of the PUBMED, Cochrane Register of Controlled Trials, MEDLINE, EMBASE, AMED, CINAHL, PsycINFO, (WoS) Web of Science, BIOSIS, LILACS and Scirus databases was conducted without language or date restrictions, and updated again current as of date of publication, with systematic reviews and meta-analyses extracted separately. Search was expanded in parallel to include just-in-time (JIT) medical feed sources as returned from Terkko (provided by the National Library of Health Sciences - Terkko at the University of Helsinki). A further "broad-spectrum" science search using Scirus (410+ million entry database) was then deployed for resources not otherwise included. Unpublished studies were located via contextual search, and relevant dissertations were located via NTLTD (Networked Digital Library of Theses and Dissertations) and OpenThesis. Sources in languages foreign to this reviewer were translated by language translation software.
References
1. Gupta GP, Massagué J. Cancer metastasis: building a framework. Cell 2006 Nov 17; 127(4):679-95.
2. Bockhorn M, Jain RK, Munn LL. Active versus passive mechanisms in metastasis: do cancer cells crawl into vessels, or are they pushed? Lancet Oncol 2007; 8(5):444-8.
3. Yang J, Mani SA, Donaher JL, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004 Jun 25; 117(7):927-39.
4. Condeelis J, Segall JE. “Intravital imaging of cell movement in tumours,” Nat Rev Cancer. 2003 Dec;3(12):921-30;
5. Wyckoff JB, Wang Y, Lin EY, et al. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res 2007 Mar 15; 67(6):2649-56.
6. Wyckoff J, Wang W, Lin EY, et al. A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res 2004 Oct 1; 64(19):7022-9.
7. Goswami S, Sahai E, Wyckoff JB, et al. Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop. Cancer Res. 2005 Jun 15;65(12):5278-83.
8. Giampieri S, Manning C, Hooper S, Jones L, Hill CS, Sahai E. Localized and reversible TGFbeta signalling switches breast cancer cells from cohesive to single cell motility. Nat Cell Biol. 2009 Nov;11(11):1287-96.
9. Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 2011; 10(6):417-27.
10. Steeg PS. Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 2006; 12(8):895-904.
11. Palumbo JS. Mechanisms linking tumor cell-associated procoagulant function to tumor dissemination. Semin Thromb Hemost 2008; 34(2):154-60.
12. Im JH, Fu W, Wang H, et al. Coagulation facilitates tumor cell spreading in the pulmonary vasculature during early metastatic colony formation. Cancer Res 2004; 64(23): 8613–8619.
13. Palumbo JS, Talmage KE, Massari JV, et al. Tumor cell-associated tissue factor and circulating hemostatic factors cooperate to increase metastatic potential through natural killer cell-dependent and -independent mechanisms. Blood 2007 110(1):133–141.
14. Khamis ZI, Sahab ZJ, Sang QX. Active roles of tumor stroma in breast cancer metastasis. Int J Breast Cancer 2012; 2012:574025.
15. Palumbo JS, Talmage KE, Massari JV, et al. Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells. Blood 2005; 105:178–85.
16. [Erpenbeck L, Schon MP. Deadly allies: the fatal interplay between platelets and metastasizing cancer cells. Blood 2010; 115:3427–36.
17. Gay LJ, Felding-Habermann B. Contribution of platelets to tumour metastasis. Nat Rev Cancer 2011; 11:123–34.
18. Degen JL , Palumbo JS . Hemostatic factors, innate immunity and malignancy. Thromb Res 2012; 129 Suppl 1:S1–5.
19. Liu Y, Jiang P, Capkova K, et al. Tissue factor activated coagulation cascade in the tumor microenvironment is critical for tumor progression and an effective target for therapy. Cancer Res 2011; 71:6492–502.]
20. Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell 2011; 20:576–90.
21. Camerer E, Qazi AA, Duong DN, Cornelissen I, Advincula R, Coughlin SR. Platelets, protease-activated receptors, and fibrinogen in hematogenous metastasis. Blood 2004;104:397–401.
22. [Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell 2011 Oct 14; 147(2):275-92.
23. Placke T, Oergel M, Schaller M, J, et al. Platelet-derived MHC Class I confers a pseudo-normal phenotype to cancer cells that subverts the anti-tumor reactivity of natural killer immune cells. Cancer Res 2012; 72:440–8.
24. Nieswandt B, Hafner M, Echtenacher B, Mannel DN. Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res 1999 59:1295–1300.
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