Reduction of metastasis in a murine mammary tumour model by heparin and polyinosinic-polycytidylic acid

Lee, A. E.; Rogers, L. A.; Longcroft, Janet M.; Jeffery, Rosemary

doi:10.1007/bf00117789

Cited by 19 publications

(13 citation statements)

References 17 publications

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“…This is likely to be due to a direct effect of heparin on the metastatic process as a number of experimental studies have confirmed that cancer progression can be influenced by heparins [31,32].…”

Section: Discussionmentioning

confidence: 99%

ICAM-1 Mediated Peritoneal Carcinomatosis, A Target for Therapeutic Intervention

Alkhamesi

Ziprin

Pfistermuller

et al. 2005

Clin Exp Metastasis

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Development of peritoneal metastasis is a significant issue in the treatment of abdominal cancers. Primary interaction between tumour cells and the mesothelium is a vital step in initiating this process. Our aim was to determine the role of the intercellular adhesion molecule-1 (ICAM-1) in mesothelial-tumour adhesion and the effectiveness of therapeutic intervention. Mesothelial cells were derived from omental tissue. ICAM-1 expression in resting state, in the presence of TNF-alpha or after the application of heparin or hyaluronan was determined by flow cytometry. Functional effects on tumour adhesion to a mesothelial monolayer were determined via a Calcein-AM in vitro adhesion assay. In vivo studies were performed utilising 30 WAG/rij rats, which underwent mini-laparotomy with the injection of 1 x 10(5 )CC 513 tumour cells intraperitoneally. Tumour growth was assessed macroscopically and microscopically by two independent examiners. Mesothelial cells expressed high level of ICAM-1, which was up-regulated by the presence of TNF-alpha. The introduction of heparin caused a decrease in ICAM-1 expression, however hyaluronan did not affect the expression. A significant decrease in tumour-mesothelial cell adhesion in vitro and complete aberration of tumour growth in vivo was observed with heparin application. In vitro studies showed utilisation of high molecular weight hyaluronan, which was more limited in vivo. These data imply that heparin may be used as a potential therapeutic through a defined molecular mechanism both in vitro and in vivo. Hyaluronan appears to function as a barrier and hence may be unreliable in blocking peritoneal recurrence.

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Section: Discussionmentioning

confidence: 99%

ICAM-1 Mediated Peritoneal Carcinomatosis, A Target for Therapeutic Intervention

Alkhamesi

Ziprin

Pfistermuller

et al. 2005

Clin Exp Metastasis

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“…Heparins were repeatedly shown to effect cancer progression, while their effect on tumor growth was rather limited [16,20,21]. Over the last twenty years, the antimetastatic activity of heparins was primarily observed in animal models of experimental metastasis (Table 1).…”

Section: Heparin Attenuates Metastasis In Animal Modelsmentioning

confidence: 99%

“…Intravenous application of heparin around the time of tumor cell injection always led to reduction of metastasis. Subcutaneous or intraperitoneal application of heparin around the time of tumor cell injection led mostly to attenuation of metastasis [11,14,20,[25][26][27], while in some studies the affectivity of heparin was limited [17,[28][29][30]. Attenuation of metastasis was repeatedly observed in most of the studies despite a wide range of heparin dosages applied (Table 1).…”

Section: Heparin Attenuates Metastasis In Animal Modelsmentioning

confidence: 99%

Antimetastatic activities of heparins and modified heparins. Experimental evidence

Borsig

2010

Thrombosis Research

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Heparin is commonly used for prevention or treatment of cancer-associated thromboembolism. Recent clinical evidence indicates that heparin, and low-molecular weight heparin improves survival of cancer patients. Experimental evidence from various animal models consistently supports the ability of heparin to attenuate metastasis. Heparin, apart from its anticoagulant activity contains a variety of biological activities possibly affecting cancer progression, including: inhibition of heparanase, blocking of P-and L-selectin mediated cell adhesion, and inhibition of angiogenesis. The delineation of antimetastatic activity of heparin is in the focus of several ongoing investigations. This review summarizes the current experimental evidence on the biology of heparin as a potential treatment cancer progression. 3

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“…The direct effect of anticoagulants on the ability of platelets to regulate angiogenesis and tumorigenesis has not been determined. [30][31][32][33][34][35][36][37][38] In most preclinical studies, the anticancer effects of LMWH and UFH did not affect the primary tumor directly, but rather reflected interference in the metastatic pathway. The publication costs of this article were defrayed in part by page charge payment.…”

Section: Introductionmentioning

confidence: 99%

Anticoagulation inhibits tumor cell–mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response

Battinelli

Markens

Kulenthirarajan

et al. 2014

Blood

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• Anticoagulants inhibit release of angiogenic proteins from platelets.Platelets are a reservoir for angiogenic proteins that are secreted in a differentially regulated process. Because of the propensity for clotting, patients with malignancy are often anticoagulated with heparin products, which paradoxically offer a survival benefit by an unknown mechanism. We hypothesized that antithrombotic agents alter the release of angiogenesis regulatory proteins from platelets. Our data revealed that platelets exposed to heparins released significantly decreased vascular endothelial growth factor (VEGF) in response to adenosine 59-diphosphate or tumor cells (MCF-7 cells) and exhibited a decreased angiogenic potential. The releasate from these platelets contained decreased proangiogenic proteins. The novel anticoagulant fondaparinux (Xa inhibitor) demonstrated a similar impact on the platelet angiogenic potential. Because these anticoagulants decrease thrombin generation, we hypothesized that they disrupt signaling through the platelet protease-activated receptor 1 (PAR1) receptor. Addition of PAR1 antagonists to platelets decreased VEGF release and angiogenic potential. Exposure to a PAR1 agonist in the presence of anticoagulants rescued the angiogenic potential. In vivo studies demonstrated that platelets from anticoagulated patients had decreased VEGF release and angiogenic potential. Our data suggest that the mechanism by which antithrombotic agents increase survival and decrease metastasis in cancer patients is through attenuation of platelet angiogenic potential. (Blood. 2014;123(1):101-112) IntroductionCancer cells are surrounded by and interact with a complex milieu consisting of but not limited to endothelial cells, mast cells, macrophages, stromal cells, and lymphocytes. In fact, tumor cells live in intimate symbiosis with the rest of the body and appear to hijack normal physiological processes to aid their progression and growth. The recognition that tumor growth and metastasis is not exclusively an independent process for tumor cells suggests that disrupting the tumor microenvironment might provide a novel treatment modality for malignancy.Although platelets are best known for their role in hemostasis and thrombosis, a substantial amount of data supports the idea that platelets play important roles in tumorigenesis, contributing to inflammation, angiogenesis, and metastatic dissemination of tumor cells.1 Platelet count can be a prognostic factor in cancer, patients presenting with thrombocytosis having a poor survival in a variety of cancers including breast cancer.2-5 Conversely, the presence of thrombocytopenia is associated with a survival benefit and decreased metastasis.6-9 For tumors to grow beyond 1 to 2 mm 3 , they must establish their own blood supply through angiogenesis, and there is substantial evidence that angiogenesis is regulated by platelets. [10][11][12] In malignancy, platelets are the major serum source of many potent proangiogenic proteins, including more than 80% of circulating vascul...

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Reduction of metastasis in a murine mammary tumour model by heparin and polyinosinic-polycytidylic acid

Cited by 19 publications

References 17 publications

ICAM-1 Mediated Peritoneal Carcinomatosis, A Target for Therapeutic Intervention

ICAM-1 Mediated Peritoneal Carcinomatosis, A Target for Therapeutic Intervention

Antimetastatic activities of heparins and modified heparins. Experimental evidence

Anticoagulation inhibits tumor cell–mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response

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