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HEMOSTASIA Y ANGIOGENESIS EN CANCER: POSIBLE NUEVO PAPEL DE LA INTERLEUQUINA 6

(especial para SIIC © Derechos reservados)

La información en conjunto indica que la interleuquina 6 es esencial en varios procesos que intervienen en la progresión tumoral.
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Autor:
Salgado R
Columnista Experto de SIIC

Artículos publicados por Salgado R
Coautores
Peter Vermeulen*  Luc Y. Dirix** 
MD, PhD. Department of Pathology, AZ. ST.-Augustinus Hospital, Oosterveldlaan 24-26. 2610 Wilrijk, Antwerp, Belgium.*
MD, PhD, Oncology Center, AZ. ST.-Augustinus Hospital, Oosterveldlaan 24-26 2610 Wilrijk, Antwerp, Belgium**
Recepción del artículo
5 de febrero, 2004 		Primera edición
7 de julio, 2004 		Segunda edición, ampliada y corregida
7 de junio, 2021
Resumen
Las complicaciones tromboembólicas a menudo se asocian con mayor mortalidad y morbilidad en pacientes con cáncer. Existen indicios de que la activación intratumoral de la coagulación tiene propiedades que promueven el crecimiento de la neoplasia. La fibrinólisis es una parte importante del remodelamiento del estroma. La fibrina es degradada por la plasmina derivada del tumor en fragmentos, entre los cuales los D-dímeros motivan el mayor interés. Estudiamos en 96 pacientes con cáncer de mama los niveles circulantes de D-dímeros. Su concentración se correlacionó en forma positiva con la carga tumoral, el número de sitios metastásicos, la cinética de progresión y las citoquinas liberadas durante la angiogénesis: VEGF sérico, carga calculada de VEGF en plaquetas y concentración sérica de interleuquina (IL) 6. En un estudio posterior medimos los factores angiogénicos circulantes, VEGF-A, IL-6 y el fragmento D-dímero de fibrina en el drenaje venoso de tumores en 21 pacientes con cáncer. Nuestros resultados sugieren que la IL-6, pero no el VEGF, deriva del tumor. En la línea celular megacarioblástica MEG-01, la expresión de VEGF-A estuvo regulada por la IL-6. Por ende, la mayor carga plaquetaria de VEGF-A que se asocia con mayor concentración sérica de VEGF en pacientes con cáncer puede ser en parte consecuencia de la mayor expresión inducida por IL-6 en los precursores plaquetarios, como megacariocitos. Posteriormente confirmamos que las plaquetas se agregan y se adhieren al endotelio tumoral. Proponemos que la IL-6 promueve en forma indirecta la angiogénesis del tumor a través de la estimulación de la producción de VEGF-A en plaquetas. Además, la correlación encontrada entre la IL-6, fibrinógeno y D-dímeros en sangre venosa periférica y la concentración elevada de D-dímero en venas de drenaje tumoral sugiere una importante contribución de la IL-6 en el metabolismo extravascular del fibrinógeno. Nuestras observaciones sugieren un papel crucial de la IL-6 en la conexión intrínseca entre hemostasia y angiogénesis.

Palabras clave
Cáncer, D-dímeros, hemostasia, IL-6, VEGF

Abstract
Thromboembolic complications are often associated with high morbidity and mortality in patients with cancer. Considerable evidence exists that intra-tumoural activation of coagulation provides growth-promoting properties to the neoplasm. Fibrinolysis is an active part of stromal remodelling. Fibrin is degraded by tumour-derived plasmin in fragments, of which D-dimers recently spurred most interest. We analysed in 96 patients with breast cancer the levels of circulating D-Dimers. D-dimer levels were positively correlated with tumour load, number of metastatic sites, progression kinetics and the cytokines related to angiogenesis: serum VEGF, calculated VEGF load in platelets and serum interleukin-6 (IL-6). In a further study we measured the circulating angiogenic factors VEGF-A, IL-6 and the fibrin D-dimer fragment in the draining veins of tumours in 21 cancer patients. Our data suggest that IL-6, but not serum VEGF is tumour-derived. In the megakaryoblastic cell line MEG-01, the expression of VEGF-A was regulated by IL-6. Thus, the higher platelet VEGF-A load resulting in higher serum VEGF levels in cancer patients may partly result from an IL-6 mediated upregulation of the expression of VEGF-A in the precursor of the platelet, i.e. the megakaryocyte. We further confirmed that platelets adhere and aggregate on tumour endothelium. We propose that IL-6 indirectly promotes tumour angiogenesis through its upregulation of the VEGF-A load in platelets. In addition, the correlations found between peripheral venous IL-6 and peripheral venous fibrinogen and D-dimers levels, and the high D-dimer levels found in the draining vein of the tumours suggest an important contribution for IL-6 in extravascular fibrinogen metabolism. Our results suggest a pivotal role for IL-6 in the intrinsic link between haemostasis and angiogenesis.

Key words
Cancer, D-dimers, haemostasis, IL-6, VEGF

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Principal: Oncología
  Relacionadas: Farmacología, Hematología, Inmunología, Medicina Interna

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Artículo completo

HAEMOSTASIS AND ANGIOGENESIS IN CANCER: AN EMERGING ROLE FOR INTERLEUKIN-6

I. Perspectives on haemostasis and cancerThromboembolic complications are often associated with high morbidity and mortality in patients with cancer.1,2 Although systemic complications of activation of haemostasis add to the adverse clinical course of patients with cancer, considerable evidence exists that intra-tumoural activation of coagulation provides additional growth-promoting properties, involving invasion and metastasis, to the neoplasm.3,4The enhanced vascular permeability in tumours facilitates extravasation of circulating coagulation factors and other circulating proteins (e.g. fibrinogen).5Fibrinogen is in normal conditions encountered only in small quantities in the extra-cellular matrix. High circulating fibrinogen levels are found in cancer patients. Tumour vessels exhibit an enhanced extravasation kinetics of fibrinogen due to the higher tumoural vascular permeability found in cancer patients. Extravasated fibrinogen is, in the pro-coagulant environment of the tumoural stroma, rapidly converted to fibrin. A fibrin matrix is considered of primary importance for angiogenesis, thus also for tumour growth.6The interaction between components of haemostasis, fibrinolysis and tumour growth is exemplified in the plasmin-plasminogen pathway. Urokinase-plasminogen activation and tissue-plasminogen activation are involved in the cellular processes associated with embryonic development, wound healing and tumour growth. The lack of tumour growth in PAI-1 deficient mice illustrates that a delicate balance between extra-cellular matrix proteolysis and inhibition of proteolysis is necessary for tumour growth.7 Breast cancer patients express high levels of these serine proteases. High intra-tumoural levels of components of the urokinase system confer a worse prognosis to cancer patients.8 The intra-tumoural concentration of urokinase-plasminogen activator is elevated and predicts a worse prognosis in patients with colon cancer.9 These observations might suggest that, beyond the mere reflection of intra-tumoural fibrinolysis, fibrin (ogen)-degradation products (FDP) are important in promoting tumour growth. They modulate the immune system and are involved in the regulation of the plasmin-plasminogen system.10,11 Pro-angiogenic properties have been described to FDP-products and they also enhance Il-6 synthesis in monocytes.12,13 Fibrinolysis is an active part of stromal remodelling.14 Fibrin is degraded by tumour-derived plasmin in several fragments, of which D-dimers recently spurred most interest.In patients with lung cancer, high levels of the fibrinolysis product, D-dimer, herald a shortened survival.15 In patients with breast cancer, high D-dimer levels are predictive for lymph node involvement, lymphovascular invasion and correlate with clinical stage.16 In patients with colorectal cancer, increased levels of D-dimers are associated with tumour size, with lymph node and hepatic metastases, with lymphatic invasion and with peritoneal dissemination. A correlation between D-dimers with stage of colon cancer suggests a relationship with tumour burden.17The before mentioned pro-coagulative environment is not only restricted to the extravascular domain of tumours. Endothelial cells also exhibit a pro-coagulative phenotype, characterised by e.g. enhanced tissue factor expression that may enhance platelet adherence and aggregation.18It has been demonstrated that platelets adhere and aggregate in the tumoural pro-coagulative environment. Remarkably, a smaller tumour volume is encountered in thrombocytopenic mice. This observation suggests a contribution of platelets in tumour growth.Definitive proof for a substantial role of platelets in promoting tumour growth is nevertheless still lacking. More evidence exists for platelets in promoting metastases. Tumour cells can promote aggregation of platelets. The platelet aggregating capability of tumour cells correlates with the metastatic potential of tumour cells. Platelet adherence on circulating tumour cells protects against the lytic activity of natural killer cells and thrombocytosis is associated with worse prognosis in patients with colorectal and lung cancer. These observations suggest that platelets may not be innocent bystanders in tumourigenesis.19,20Others and we have accumulated evidence for a role of platelets as major transporters of VEGF. Platelets of cancer patients have, compared with healthy controls, a higher platelet VEGF load.21 The biological significance of a higher platelet VEGF load in patients with cancer is not clear. Pinedo et al. postulated a role of platelets in promoting angiogenesis through local release of pro-angiogenic molecules (e.g.; VEGF, bFGF, PDGF). Although platelets have anti-angiogenic proteins (TSP-1, PF-4) a net pro-angiogenic effect has been demonstrated.22,23

II. Highlights and future perspectives of "Plasma fibrin D-dimer levels correlate with tumour volume, progression rate and survival in patients with metastatic breast cancer"
(Dirix et al., Br. J. Cancer, 2002)We have investigated in this study the relationship between the markers of fibrin metabolism, (D-dimers), standard clinicopathological variables and serum levels of angiogenic cytokines (IL-6 and Vascular Endothelial Growth Factor–VEGF) in three cohorts: group A (n = 30) consisted of 30 healthy female volunteers, group B (n = 23) of consecutive patients with operable breast cancer and group C (n = 84) of patients with untreated or progressive metastatic breast cancer. Plasma D-dimers, fibrinogen, IL-6, VEGF and calculated VEGF load in platelets are clearly increased in patients with breast cancer. D-dimers were increased in nearly 89% of patients with progressive metastatic disease. The level of D-dimers was positively correlated with tumour load (p < 0.0001), number of metastatic sites (p = 0.002), progression kinetics (p < 0.0001) and the cytokines related to angiogenesis: serum VEGF (p = 0.0016, Spearman correlation = 0.285), calculated VEGF load in platelets (p < 0.0001, Spearman correlation =0.37) and serum interleukin-6 (p < 0.0001, Spearman correlation = 0.59). Similarly increased D-dimer levels were positively correlated with increased fibrinogen levels (p < 0.0001, Spearman correlation = 0.38). The association between markers of fibrin degradation in patients with progressive breast cancer suggests that the D-dimer level is a clinically important marker for progression and points towards a relation between haemostasis and tumour progression. A role of interleukin-6, by influencing both angiogenesis and haemostasis, is suggested by these observations.24In a further study25 we measured the circulating angiogenic factors VEGF-A, IL-6 and the fibrin D-dimer fragment in the mesenteric vein, the uterine vein, as well as in peripheral venous and arterial samples in 21 randomly selected patients with operable colorectal, ovarian and cervical carcinoma in order to elucidate the origin of these angiogenic factors generally found to be elevated in patients with cancer. In addition, immunohistochemistry for VEGF-A and IL-6 was performed on colorectal tumours of these patients. Serum and plasma VEGF-A were not significantly elevated in the vein draining the tumours, despite tumour cell expression of VEGF-A. Serum VEGF is therefore not all tumour-derived. In contrast, serum IL-6 was highly elevated in the draining veins in agreement with expression of IL-6 in the cytoplasm of tumour cells. In the megakaryoblastic cell line MEG-01, the expression of VEGF-A was found to be regulated by IL-6. Thus, the higher platelet VEGF-A load resulting in higher serum VEGF levels in cancer patients may partly result from an IL-6 mediated upregulation of the expression of VEGF-A in the precursor of the platelet, i.e. the megakaryocyte. We next performed an immunohistochemical analysis of platelets and fibrin in tumours in order to provide further evidence of intra-tumoural haemostasis. We confirmed by immunohistochemistry that platelets adhere and aggregate on tumour endothelium. We propose that IL-6 indirectly promotes tumour angiogenesis through its upregulation of the VEGF-A load in platelets. In addition, the correlations found between peripheral venous IL-6 and peripheral venous fibrinogen and D-dimers levels, and the high D-dimer levels found in the draining vein of the tumour, in agreement with fibrin deposits found in the tumour stroma, suggest an important role for IL-6 in extravascular fibrinogen metabolism. Our results suggest a pivotal role for IL-6 in the intrinsic link between haemostasis and angiogenesis.

III. Angiogenesis and Haemostasis in cancer: two sides of a flip coin

As already mentioned, components of haemostasis (e.g. tissue factor, thrombomodulin, thrombin) have important roles beyond the mere regulation of haemostasis. These factors are involved in physiological conditions, e.g. wound healing and in the menstrual cycle; and in pathophysiological conditions, e.g. atherosclerosis and cancer. Regulation of tissue integrity is considered to be not only dependent on an adequate supply of nourishing factors by newly formed blood vessels, with a corresponding removal of waste products. Autocrine- and paracrine interactions between growth factors produced by blood vessels and other cells, e.g. fibroblasts, add to the functionality of these proceses.26,27A striking functional redundancy exists for growth factors associated with angiogenesis beyond merely inducing endothelial cell proliferation, migration and differentiation. Tumour cell secreted VEGF-A has not only been involved in the intra-tumoural immune-regulation, but also in the induction of the principal activator of the extrinsic system of coagulation: tissue factor. This effect is mediated by VEGF-A-induced binding of the transcription factor EGR-1 at the tissue factor promotor site. High levels of tissue factor are, independent of its clotting-inducible property, mitogenic for endothelial cells. A decreased expression of tissue factor in tumour cells leads to decreased VEGF-A expression and increased expression of Thrombospondin-1, which is associated with inhibition of angiogenesis.28,29 Moreover, VEGF production in fibroblasts after binding factor VIIa to tissue factor seems to involve thrombin and factor Xa.30 Interestingly, both factor VIIa and thrombin are capable of inducing the expression of extra-cellular matrix proteins Cyr61 and connective tissue growth factor.31These examples illustrate that haemostasis and angiogenesis are two sides of a flip coin implicated in concert in tissue remoddeling. Both are intrinsically linked and cannot occur separately in vivo.The activation of haemostasis and of angiogenesis are caused by the interplay between varieties of cells: tumour cells, mononuclear macrophages, platelets and stromal cells, e.g. fibroblasts and endothelial cells with a corresponding cell-surface activation of coagulation factors. We propose a cell-based model of activation of intra-tumoural haemostasis and angiogenesis in the context of promoting tumour growth (Figure 1). The growth promoting properties associated with activation of haemostasis intra-tumourally are caused by interplay of haemostasis and angiogenesis involved in 1) tumour cell-associated effects, e.g. proliferation, invasion and survival; 2) stromal remodelling effects, e.g. the formation of a provisional fibrin matrix associated with cell migration and survival; 3) enhancement of new vessel formation and 4) involvement of platelet-VEGF in promoting angiogenesis.
Figure 1.An overview of hypothetical interactions between haemostasis and angiogenesis mediating tumour growth is given. It should be emphasized that stromal cells (fibroblasts, smooth muscle cells, macrophages) contribute also to the activation of coagulation and angiogenesis. These cells are, due to space limitations, not illustrated. Tumour cell produced Interleukin-6 causes higher circulating fibrinogen levels through the enhanced induction of fibrinogen expression and secretion in hepatic cells. Since VEGF-A enhances vascular permeability in tumoural blood vessels, extravasation of circulating proteins (e.g. coagulation factors, vitronectin and fibrinogen) occurs. Fibrinogen-fibrin metabolism occurs with the formation of fibrin- (ogen) degradation products, which may influence tumour growth through a direct or indirect effect on endothelial or tumour cells. Platelet adherence, aggregation and eventually extravasation occur and platelets release their VEGF-A content on endothelium and on tumour cells. The platelet VEGF-A load may origin form endocytosis of tumour cell produced VEGF-A and/or may be derived through an tumour cell mediated IL-6 enhanced expression of VEGF-A in the platelet precursors, the megakaryocytes. Tumour cell and platelet derived VEGF-A may contribute, by e.g. enhancing Tissue Factor expression, further to the activation of coagulation and cellular (e.g. endothelial) activation by coagulation factors (e.g. factor X or thrombin). Intravasated tumour cell derived or platelet released VEGF may be scavenged by platelets and/ or endothelium released soluble VEGF-A receptors. Reciprocal interaction between IL-6 mediated modulation of haemostasis and angiogenesis in primary tumours may provide with an adequate environment for migration, proliferation and intravasation of tumour cells in areas of relative high vessel density.
Hypoxia proves to be of utmost importance in the context of the intrinsically linked haemostasis and angiogenesis processes. Several molecules of haemostasis (e.g. PAI-1, uPA, uPAR, TF) and angiogenesis (e.g. angiogenin, angiopoeitin-2, VEGF, VEGF-B) are upregulated by hypoxia.32,33 Hypoxia induces VEGF, tissue factor (TF) and IL-6 expression in a variety of cells. VEGF induces TF-expression, and vice versa. IL-6 induces TF and VEGF and the latter is in turn able to modulate IL-6 expression. Interleukin-6 is therefore an illustrative example of a molecule linking haemostasis and angiogenesis in the context of hypoxia-mediated tumour growth.

IV. Role of IL-6 in linking angiogenesis and haemostasis in cancer: the concept of local and distant regulation of tumour growth

One of the most important issues in current research concerns the endocrine regulation of tumour angiogenesis.34,35 This may provoke an important paradigm shift in the concept that tumour growth is not only regulated locally, but may also be regulated by molecules derived at distant sites. An example of an endocrine activity of tumour cells is the observation of a higher endothelial cell proliferation in the cornea of patients with solid tumours, compared with the endothelial cell proliferation in patients without solid tumours.36 Moreover, the expression of these distant acting tumour-derived molecules, which in turn may enhance the growth of the tumours and/or metastasis, mechanistically explained as a positive feedback mechanism, is not only novel but may have significant implications in the development of anti-tumour agents and in the evaluation of the anti-tumour response in clinical trials evaluating anti-angiogenesis products.Our results indicate that circulating levels of IL-6, and not VEGF-A, are derived from the tumour. This observation does not rule out that IL-6 and VEGF are not involved in the regulation of intra-tumoural angiogenesis, but rather indicates that the bio-availability of both tumour cell-produced VEGF and IL-6 in the extra-cellular matrix may be different. The members of the VEGF-A family have different affinities for e.g. heparan sulphate proteoglycans in the extra-cellular matrix, and may therefore be less prone to be released in the circulation. This does not rule out that no VEGF is released in the systemic circulation, but suggest that most of circulating VEGF is derived from a different source.We provide evidence that circulating VEGF is partly derived from IL-6 mediated enhancement of VEGF-expression in the platelet precursors, the megakaryocytes. This indicates an intrinsic relation between the tumour and bone marrow. An illustrative example of interactions between a primary tumour and bone marrow is the anecdotal observation that in a patient with a renal cell carcinoma and multiple myeloma, progression of the latter slowed down after resection of the renal cell carcinoma.37 Renal cell carcinoma is known to produce and release high levels of IL-6 in the systemic circulation.38 This might indicate that, since the progression of multiple myeloma is IL-6 dependent, circulating IL-6 is bioactive and is able to modulate progression of bone marrow residing tumours.This finding might suggest that tumour derived IL-6 is bioactive and able to modulate VEGF expression in megakaryocytes. Platelets of cancer patients acquire thus a higher VEGF content during tumour progression. Several authors have demonstrated that the VEGF contained within the platelets, is bioactive and able to modulate endothelial cell behaviour.22,39,40 A high platelet VEGF load is associated with worse prognosis in patients with renal cancer.41 This is a mere statistical observation, while the authors provided no convincing data explaining this finding. The importance of the platelet VEGF load may be deduced by the local adherence and aggregation of platelets at pro-coagulative sites. This pro-coagulative environment is found in tumours. Platelets may adhere and aggregate on tumoural endothelium and this is associated with the invariable local release of the IL-6-mediated high VEGF levels found in the platelet -granules. Local release of VEGF might therefore promote angiogenesis, thus tumour growth, providing thus with a partial explanation as to why a fast tumour doubling time is associated with both platelet count as well as with a high platelet VEGF load. This may also explain the worse prognosis associated with a high platelet VEGF load in patients with renal cancer, which by itself is recognised as being partly IL-6-dependent for tumour progression. The example of tumour-derived IL-6 able to modulate the platelet VEGF-load in the bone marrow of cancer patients in turn providing addition stimulus for ongoing intra-tumoural angiogenesis, is illustrative for the concept of positive dynamic endocrine interactions between a tumour site and distant organs (figure 1).The emerging data on the contribution of bone marrow derived endothelials and their precursors to the intra-tumoural vascularisation is in line with our observations, suggesting a cross talk between tumour and bone marrow.The clear-cut association between the platelet VEGF load and serum VEGF elaborated considerable discussion whether measuring plasma VEGF would reflect more ongoing angiogenesis in patients with cancer than serum VEGF. We think that the answer needs to be in complete accordance with the model proposed. Ongoing angiogenesis is modulated locally as well as by distant sites, and measuring serum levels, that contains cell-bound VEGF and free VEGF, or lysates of whole blood might be more feasible than plasma VEGF. Moreover, plasma VEGF may be biased if a rigorous methodology of blood sampling is not used in order to avoid platelet activation.For the moment, however, no definitive answer can be given. Prospective and well-designed studies need to be performed comparing whole blood lysates, serum and plasma VEGF, in order to optimise the methodology and to discern which parameter is more able to yield reliable and reproducible predictive and prognostic information in patients with cancer.The concept that a tumour growth enhances the expression of factors at distant sites that in turn may modulate tumour growth is not limited to tumour-bone marrow interactions.Interleukin-6 is known to mediate circulating levels of fibrinogen. It enhances the expression of fibrinogen in hepatic cells.42 Since tumour cell, stromal cell or platelet-derived VEGF is able to enhance the vascular permeability of tumours, extravasation of circulating fibrinogen and other coagulation factors occurs. Fibrinolysis is an integral part of tumour-associated remodelling of the stroma and fibrin degradation occurs with subsequent release of fibrin-degradation products (FDP) in the circulation. In addition, intra-tumoural fibrinolysis-derived fibrin-degradation products (FDP's) are associated with fast tumour growth kinetics and worse prognosis.There are several observations linking the mere formation and presence of FDP's with modulation of angiogenesis and immunity and fibrinolysis among others. Thus, IL-6 is able to modulate the VEGF-load in platelets of cancer patients that will adhere and release VEGF on tumoural endothelium causing an enhanced vascular permeability, which will enable the extravasation of IL-6-mediated circulating fibrinogen levels. In a previous study (unpublished observations) we did not find massive platelet consumption in tumours as assessed by measurement of the platelet turnover marker, glycocalicin, in efferent venous blood of colon tumours. No massive consumption of platelets in tumours is compatible with some animal models where no massive adhesion of platelets is demonstrated in the vasculature of implanted tumours. Increased platelet rolling though reduced platelet-endothelial interactions were the main findings in this model.43 With immunohistochemistry we did find adherence of platelets on tumoural endothelium, which is probably reflected by the enhanced exposure and binding of platelets onto sub-endothelial tissue in hyperpermeable vessels in human tumours. Both findings, no massive consumption and local adherence and aggregation, can be reconciled, however. First, platelet do adhere, but do not aggregate, and promote endothelial cell survival of newly formed vessels. No massive aggregation of platelets would be evident in this case. Second, in areas with enhanced vascular permeability and pro-coagulative endothelium, platelets could adhere, aggregate and release their angiogenic content in the environment.The importance of microvascular tumour permeability is corroborated by recent findings demonstrating that blocking the cell-permeable peptide derived from caveolin-1, cavtratin, reduces significantly the hyperpermeability of tumours and delays tumour growth in mice.44Since IL-6 and VEGF enhance the expression of TF, thus coagulation, thrombin is formed enabling the formation of fibrin and subsequent fibrinolyis intra-tumourally. IL-6 is thus central in both tumour-bone marrow and tumour-liver mediated endocrine interactions that enable the formation of VEGF and fibrinogen which are essential for the ongoing stromal remodelling process associated with tumour growth (Figure 1).The findings mentioned above may provide part of the explanation for the worse prognosis associated with high circulating levels of IL-6 and D-Dimers in patients with breast cancer.

V. Is the Trousseau's phenomenon the Achilles' heel of cancer

Our observation that haemostasis is important for tumour growth is not novel. Several reports have demonstrated an importance of haemostasis for tumour growth. These findings have prompted clinical trials with anti-haemostatic factors, e.g. heparin in cancer patients in order to improve prognosis.45,46 Conflicting results have however been obtained. This reflects not only the inadequacies of the methodologies used- most of these studies were retrospective-, but also the different haemostatics profile of different tumours.The importance of angiogenesis for tumour growth is not novel either. Several reports have highlighted the prognostic and predictive value of measuring angiogenesis in tumours. This has also primed interest in the development of anti-angiogenic agents.47 Here also conflicting results have been obtained. This might reflect our incomplete knowledge of angiogenesis in general and of the targets in particular.Our results demonstrate that endocrine regulation of angiogenesis involves modulation of both haemostasis and angiogenesis. Targeting a tumour locally could result in a diminished production of e.g. IL-6 locally, and thus reduced induction of factors, e.g. VEGF and fibrinogen, at distant sites that consequently could affect tumour growth at the primary site.The proposed concept of distant modulation of local tumoural growth processes, also elicits importance in the measurement of circulating factors, e.g. serum VEGF, as a measure of response to therapy not only locally but also as a measure of reduced distant induction by the tumour itself in e.g. clinical anti-angiogenesis trials.Our data suggest that targeting angiogenesis, e.g. with VEGF-receptor tyrosine kinase inhibitors, will affect haemostasis and targeting haemostasis, e.g. with heparin, will affect angiogenesis both directly and indirectly.Whether targeting both simultaneously, with e.g. the combination of an anti-angiogenic agent- TNP-470- and e.g. a, inhibitor of platelet aggregation- will add to the therapeutic potency compared with single administration, cannot be deduced from the data obtained so far. Proper development of agents against haemostatic and/or angiogenesis targets will depend on an adequate knowledge of the targets involved in order to design proper trials. Whether targeting IL-6 is feasible needs still to be determined. Since our knowledge of IL-6 in tumour growth is incomplete, targeting of IL-6 is not an option to consider so far. In several animal models it has been shown that inhibiting IL-6 will promote, inhibit or will have no effect on the growth of transplanted tumours. In humans the role of IL-6 in most tumours is not clear at all. Several question remain to be answered: 1) at what stage during tumour progression will IL-6 be upregulated; 2) could our findings be extrapolated to all tumours, 3) is the platelet VEGF load also enhanced in patients with cancers that does not produce high IL-6, 4) at what stage of tumour progression does haemostasis get activated, 5) is haemostasis important for all tumours, 6) how is IL-6 involved in the different vascularisation models described so far, 7) will adding IL-6 to patients with chemotherapy-induced platelet depression alter the prognosis, if so what is the pathophysiology of it, 8) is the outgrowth of micro-metastases into overtly detectable metastases influenced by platelets, 9) are metastases also haemostasis- and angiogenesis-dependent in a comparable manner with their primary tumour All these questions need to be answered before targeting the systemic nature of cancer by inhibiting IL-6 will become an option to consider.
Bibliografía del artículo
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