Thrombin inhibition and cyclophosphamide synergistically block tumor progression and metastasis

Alexander, Eric T.; Minton, Allyson R.; Hayes, Candace S.; Goss, Ashley; Ryn, Joanne van; Gilmour, Susan K.

doi:10.1080/15384047.2015.1078025

Cited by 31 publications

(48 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a murine model of breast tumour, the combined use of cyclophosphamide or CP and dabigatran etexilate, a direct inhibitor of thrombin, showed a significant synergistic effect. The tumours were significantly smaller and produced less pulmonary metastases when compared to mice only treated with one of the drugs [98]. Patients with triple-negative breast cancer for oesterogen receptor (ER)-, progesterone receptor (PR),- and HER2- have a poor prognosis as they frequently develop metastasis.…”

Section: Metastasis In Target Organsmentioning

confidence: 99%

Cancer and the metastatic substrate

Arvelo¹,

Sojo²,

Cotte³

2016

ecancer

View full text Add to dashboard Cite

Seventy percent of cancer patients have detectable metastases when they receive a diagnosis and 90% of cancer deaths result from metastases. These two facts emphasise the urgency for research to study the mechanisms and processes that enable metastasis. We need to develop a greater understanding of the cellular and molecular mechanisms that cause metastasis and also we need to do more. We must also consider the micro- and macro-environmental factors that influence this disease. Studying this environmental context has led us to update the ‘seed and soil’ hypothesis which dates back to the 19th century. This theory describes cancerous cells as seeds and the substrate as the soil in target organs though this may seem antiquated. Nonetheless, the tissue specificity that researchers have recently observed in metastatic colonisation supports the validity of the seed and soil theory. We now know that the metastatic potential of a tumour cell depends on multiple, reciprocal interactions between the primary tumour and distant sites. These interactions determine tumour progression. Studies of metastasis have allowed us to develop treatments that focus on therapeutic effectiveness. These new treatments account for the frequent metastasis of some tumours to target organs such as bones, lungs, brain, and liver. The purpose of this review is first to describe interactions between the cellular and molecular entities and the target organ tumour environment that enables metastasis. A second aim is to describe the complex mechanisms that mediate these interactions.

show abstract

Section: Metastasis In Target Organsmentioning

confidence: 99%

Cancer and the metastatic substrate

Arvelo¹,

Sojo²,

Cotte³

2016

ecancer

View full text Add to dashboard Cite

show abstract

“…Dabigatran etexilate decreased tumor volume by 50 % and reduced both 4T1 tumor cells in the blood and liver micrometastases by 50-60 % [27]. Mice receiving cotreatment with both low dose cyclophosphamide (CP) and dabigatran etexilate had significantly smaller mammary tumors and fewer lung metastases than mice treated with CP or dabigatran etexilate alone [25]. Treatment with dabigatran etexilate alone prevented tumor-induced increases in circulating TF(+) microparticles and also decreased the numbers of tumor-induced activated platelets by 40 % suggesting that thrombin plays a strong role in intravascular events.…”

Section: In Vivo Evidence Of Secondary Lesionsmentioning

confidence: 95%

“…Studies with dabigatran etexilate, a direct inhibitor of thrombin, are also promising [25,27]. In animal models, oral administration of dabigatran etexilate inhibits both invasion and metastasis of malignant breast and prostate tumors.…”

Section: In Vivo Evidence Of Secondary Lesionsmentioning

confidence: 98%

“…Therefore, TF, expressed at the cell membrane on most tumors as well as on tumor vasculature and within the tumor microenvironment on stem cells, macrophages, ECs, and myofibroblasts, likely contributes to thrombin production [45][46][47][48][49][50][51]. Tumor microparticles such as exosomes may also display TF and induce thrombin generation [25], as byproducts such as these particles can enter general circulation via the abnormal, leaky blood vessels that are formed during tumor growth [52][53][54]. In addition to tumor cell-associated thrombin production, the components of the endothelium itself, including the endothelial cell protein TM, can regulate thrombin generation/activity to affect the metastatic process [26].…”

Section: 1 Thrombin Generation Within the Host-tumor-environmentmentioning

confidence: 99%

“…Many thrombin or thrombin-dependent substrate inhibitors have been investigated. However, none have been incorporated into clinical oncology practice [19,[25][26][27][28].…”

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

Thrombin—unique coagulation system protein with multifaceted impacts on cancer and metastasis

Wojtukiewicz

Hempel

Sierko

et al. 2016

Cancer Metastasis Rev

View full text Add to dashboard Cite

The association between blood coagulation and cancer development is well recognized. Thrombin, the pleiotropic enzyme best known for its contribution to fibrin formation and platelet aggregation during vascular hemostasis, may also trigger cellular events through protease-activated receptors, PAR-1 and PAR-4, leading to cancer progression. Our pioneering findings provided evidence that thrombin contributes to cancer metastasis by increasing adhesive potential of malignant cells. However, there is evidence that thrombin regulates every step of cancer dissemination: (1) cancer cell invasion, detachment from primary tumor, migration; (2) entering the blood vessel; (3) surviving in vasculature; (4) extravasation; (5) implantation in host organs. Recent studies have provided new molecular data about thrombin generation in cancer patients and the mechanisms by which thrombin contributes to transendothelial migration, platelet/tumor cell interactions, angiogenesis, and other processes. Though a great deal is known regarding the role of thrombin in cancer dissemination, there are new data for multiple thrombin-mediated events that justify devoting focus to this topic with a comprehensive approach.

show abstract

Immunomodulatory role of thrombin in cancer progression

Alexander

Gilmour

2022

Molecular Carcinogenesis

View full text Add to dashboard Cite

Coagulation proteases and the generation of thrombin are increased in tumors. In addition, chemotherapeutic agents commonly used to treat malignant cancers can exacerbate cancer‐associated thromboses. Thrombin can modify tumor cell behavior directly through the activation of protease‐activated receptors (PAR) or indirectly by generating fibrin matrices. In addition to its role in generating fibrin to promote hemostasis, thrombin acts directly on multiple effector cells of the immune system impacting both acute and chronic inflammatory processes. Thrombin‐mediated release of interleukin‐6, tumor necrosis factor‐α, and monocyte chemoattractant protein‐1 leads to the accumulation of multiple tumor‐infiltrating immunosuppressive cell populations including myeloid derived suppresser cells, M2‐like macrophages, and T regulatory cells. Ablation of PAR‐1 from the tumor microenvironment, but not the tumor, has been shown to dramatically reduce tumor growth and metastasis in multiple tumor models. Thrombin‐activated platelets release immunosuppressive cytokines including transforming growth factor‐β that can inhibit natural killer cell activity, helping tumor cells to evade host immunosurveillance. Taken together, there is strong evidence that thrombin influences cancer progression via multiple mechanisms, including the tumor immune response, with thrombin emerging as a target for novel therapeutic strategies for cancer.

show abstract

Thrombin inhibition and cyclophosphamide synergistically block tumor progression and metastasis

Cited by 31 publications

References 66 publications

Cancer and the metastatic substrate

Cancer and the metastatic substrate

Thrombin—unique coagulation system protein with multifaceted impacts on cancer and metastasis

Immunomodulatory role of thrombin in cancer progression

Contact Info

Product

Resources

About