Activation of coagulation and angiogenesis in cancer: Immunohistochemical localization in situ of clotting proteins and vascular endothelial growth factor in human cancer

Mamoru Shoji, Wayne W. Hancock, Keisuke Abe, Cornelia Micko, Katherine A. Casper, Rosalie M. Baine, Josiah N. Wilcox, Indrani Danave, Dirck L. Dillehay, Eileen Matthews, Josephine Contrino, James H. Morrissey, Stuart Gordon, Thomas S. Edgington, Bohdan Kudryk, Donald L. Kreutzer, Frederick R. Rickles

Research output: Contribution to journalArticle

Abstract

Thrombin-catalyzed, cross-linked fibrin (XLF) formation is a characteristic histopathological finding in many human and experimental tumors and is thought to be of importance in the local host defense response. Although the pathogenesis of tumor-associated fibrin deposition is not entirely clear, several tumor procoagulants have been described as likely primary stimuli for the generation of thrombin (and XLF) in the tumor microenvironment (TME). In a previous study of a variety of human tumors we have shown that tissue factor (TF) is the major procoagulant. However, the relative contribution to fibrin deposition in the TME of tumor cell TF and host cell TF (eg, macrophage-derived) was not established. In addition, recent evidence has implicated TF in the regulation of the synthesis of the pro-angiogenic factor vascular endothelial growth factor (VEGF) by tumor cells. In the current study we used in situ techniques to determine the cellular localization of XLF, TF, VEGF, and an alternative tumor procoagulant, so-called cancer procoagulant (CP), a cysteine protease that activates clotting factor X. In lung cancer we have found XLF localized predominantly to the surface of tumor-associated macrophages, as well as to some endothelial cells and perivascular fibroblasts in the stromal area of the tumors co-distributed with TF at the interface of the tumor and host cells. Cancer procoagulant was localized to tumor cells in several cases but not in conjunction with the deposition of XLF. TF and VEGF were co-localized in both lung cancer and breast cancer cells by in situ hybridization and immunohistochemical staining. Furthermore, a strong relationship was found between the synthesis of TF and VEGF levels in human breast cancer cell lines (r2 = 0.84; P < 0.0001). Taken together, these data are consistent with a highly complex interaction between tumor cells, macrophages, and endothelial cells in the TME leading to fibrin formation and tumor angiogenesis.

Original languageEnglish (US)
Pages (from-to)399-411
Number of pages13
JournalAmerican Journal of Pathology
Volume152
Issue number2
StatePublished - Feb 1 1998

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Thromboplastin
Neoplasms
Proteins
cancer procoagulant
Fibrin
Vascular Endothelial Growth Factor A
Tumor Microenvironment
Macrophages
Breast Neoplasms
Thrombin
human VEGFA protein
Lung Neoplasms
Endothelial Cells
Factor X
Blood Coagulation Factors
Cysteine Proteases
Angiogenesis Inducing Agents
In Situ Hybridization
Fibroblasts
Staining and Labeling

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Activation of coagulation and angiogenesis in cancer : Immunohistochemical localization in situ of clotting proteins and vascular endothelial growth factor in human cancer. / Shoji, Mamoru; Hancock, Wayne W.; Abe, Keisuke; Micko, Cornelia; Casper, Katherine A.; Baine, Rosalie M.; Wilcox, Josiah N.; Danave, Indrani; Dillehay, Dirck L.; Matthews, Eileen; Contrino, Josephine; Morrissey, James H.; Gordon, Stuart; Edgington, Thomas S.; Kudryk, Bohdan; Kreutzer, Donald L.; Rickles, Frederick R.

In: American Journal of Pathology, Vol. 152, No. 2, 01.02.1998, p. 399-411.

Research output: Contribution to journalArticle

Shoji, M, Hancock, WW, Abe, K, Micko, C, Casper, KA, Baine, RM, Wilcox, JN, Danave, I, Dillehay, DL, Matthews, E, Contrino, J, Morrissey, JH, Gordon, S, Edgington, TS, Kudryk, B, Kreutzer, DL & Rickles, FR 1998, 'Activation of coagulation and angiogenesis in cancer: Immunohistochemical localization in situ of clotting proteins and vascular endothelial growth factor in human cancer', American Journal of Pathology, vol. 152, no. 2, pp. 399-411.
Shoji, Mamoru ; Hancock, Wayne W. ; Abe, Keisuke ; Micko, Cornelia ; Casper, Katherine A. ; Baine, Rosalie M. ; Wilcox, Josiah N. ; Danave, Indrani ; Dillehay, Dirck L. ; Matthews, Eileen ; Contrino, Josephine ; Morrissey, James H. ; Gordon, Stuart ; Edgington, Thomas S. ; Kudryk, Bohdan ; Kreutzer, Donald L. ; Rickles, Frederick R. / Activation of coagulation and angiogenesis in cancer : Immunohistochemical localization in situ of clotting proteins and vascular endothelial growth factor in human cancer. In: American Journal of Pathology. 1998 ; Vol. 152, No. 2. pp. 399-411.
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abstract = "Thrombin-catalyzed, cross-linked fibrin (XLF) formation is a characteristic histopathological finding in many human and experimental tumors and is thought to be of importance in the local host defense response. Although the pathogenesis of tumor-associated fibrin deposition is not entirely clear, several tumor procoagulants have been described as likely primary stimuli for the generation of thrombin (and XLF) in the tumor microenvironment (TME). In a previous study of a variety of human tumors we have shown that tissue factor (TF) is the major procoagulant. However, the relative contribution to fibrin deposition in the TME of tumor cell TF and host cell TF (eg, macrophage-derived) was not established. In addition, recent evidence has implicated TF in the regulation of the synthesis of the pro-angiogenic factor vascular endothelial growth factor (VEGF) by tumor cells. In the current study we used in situ techniques to determine the cellular localization of XLF, TF, VEGF, and an alternative tumor procoagulant, so-called cancer procoagulant (CP), a cysteine protease that activates clotting factor X. In lung cancer we have found XLF localized predominantly to the surface of tumor-associated macrophages, as well as to some endothelial cells and perivascular fibroblasts in the stromal area of the tumors co-distributed with TF at the interface of the tumor and host cells. Cancer procoagulant was localized to tumor cells in several cases but not in conjunction with the deposition of XLF. TF and VEGF were co-localized in both lung cancer and breast cancer cells by in situ hybridization and immunohistochemical staining. Furthermore, a strong relationship was found between the synthesis of TF and VEGF levels in human breast cancer cell lines (r2 = 0.84; P < 0.0001). Taken together, these data are consistent with a highly complex interaction between tumor cells, macrophages, and endothelial cells in the TME leading to fibrin formation and tumor angiogenesis.",
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T2 - Immunohistochemical localization in situ of clotting proteins and vascular endothelial growth factor in human cancer

AU - Shoji, Mamoru

AU - Hancock, Wayne W.

AU - Abe, Keisuke

AU - Micko, Cornelia

AU - Casper, Katherine A.

AU - Baine, Rosalie M.

AU - Wilcox, Josiah N.

AU - Danave, Indrani

AU - Dillehay, Dirck L.

AU - Matthews, Eileen

AU - Contrino, Josephine

AU - Morrissey, James H.

AU - Gordon, Stuart

AU - Edgington, Thomas S.

AU - Kudryk, Bohdan

AU - Kreutzer, Donald L.

AU - Rickles, Frederick R.

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N2 - Thrombin-catalyzed, cross-linked fibrin (XLF) formation is a characteristic histopathological finding in many human and experimental tumors and is thought to be of importance in the local host defense response. Although the pathogenesis of tumor-associated fibrin deposition is not entirely clear, several tumor procoagulants have been described as likely primary stimuli for the generation of thrombin (and XLF) in the tumor microenvironment (TME). In a previous study of a variety of human tumors we have shown that tissue factor (TF) is the major procoagulant. However, the relative contribution to fibrin deposition in the TME of tumor cell TF and host cell TF (eg, macrophage-derived) was not established. In addition, recent evidence has implicated TF in the regulation of the synthesis of the pro-angiogenic factor vascular endothelial growth factor (VEGF) by tumor cells. In the current study we used in situ techniques to determine the cellular localization of XLF, TF, VEGF, and an alternative tumor procoagulant, so-called cancer procoagulant (CP), a cysteine protease that activates clotting factor X. In lung cancer we have found XLF localized predominantly to the surface of tumor-associated macrophages, as well as to some endothelial cells and perivascular fibroblasts in the stromal area of the tumors co-distributed with TF at the interface of the tumor and host cells. Cancer procoagulant was localized to tumor cells in several cases but not in conjunction with the deposition of XLF. TF and VEGF were co-localized in both lung cancer and breast cancer cells by in situ hybridization and immunohistochemical staining. Furthermore, a strong relationship was found between the synthesis of TF and VEGF levels in human breast cancer cell lines (r2 = 0.84; P < 0.0001). Taken together, these data are consistent with a highly complex interaction between tumor cells, macrophages, and endothelial cells in the TME leading to fibrin formation and tumor angiogenesis.

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