Blood, 15 November 2000, Vol. 96, No. 10, pp. 3301-3301
FOCUS ON HEMATOLOGY
Introduction: fibrinogen as a determinant of the metastatic
potential of tumor cells
Michael W. Mosesson
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Article |
An association between the hemostatic system and
cancer has been well known for many years. Hemostatic complications are
a common cause of death in patients with cancer, and abnormalities such
as disseminated intravascular coagulation and migratory
thrombophlebitis have been well described. Many tumor cells possess
procoagulant activities that promote local activation of the
coagulation system, and tumor-mediated activation of the coagulation
cascade has been implicated in both tumor stroma formation and the
promotion of hematogenous metastasis.1,2 Most solid human
and experimental animal tumors contain considerable amounts of
fibrinogen-related products, suggesting that fibrin (ogen) is
important in stroma formation. Fibrin clots promote migration of
several types of cells, including endothelial cells, macrophages, and
fibroblasts.1,3,4 Fibrin also promotes neovascularization,
supporting the notion that fibrin facilitates tumor stroma formation by
mechanisms that are analogous to those in wound repair. Fibrin
degradation products display powerful chemotactic, immunomodulatory,
and angiogenic properties. Thus, substantial evidence points to a
significant role for fibrin(ogen) in tumor progression. The coagulation
system has also been implicated in hematogenous tumor cell spread.
Following their entry into the circulation, tumor cells must adhere to
the microvasculature of a target organ prior to growth. Deposition of
fibrin within adherent tumor cell aggregates can be detected shortly
after tumor cell inoculation and persists for several hours.5,6
The generation of viable mouse lines with selected deficits in key
hemostatic factors has provided an opportunity to directly examine the
role of fibrin(ogen) in tumor progression and spread. In this Focus on
Hematology, Palumbo and colleagues used fibrinogen-deficient and
plasminogen-deficient transgenic mice and two transplantable murine
tumor cell lines, Lewis lung carcinoma and B16-BL6 melanoma, to
determine the effects of these deficiencies on hematogenous pulmonary
metastastes. Fibrinogen deficiency did not reduce the growth rate of
transplanted Lewis lung carcinoma, and Lewis lung carcinoma and B16
melanoma cells were also capable of establishing pulmonary metastatic
foci in fibrinogen-deficient mice comparable to those observed in
nondeficient mice. Thus, fibrinogen was not strictly required for
hematogenous metastases, but fibrinogen deficiency strongly diminished
the metastatic capacity of either type of tumor, because
fibrinogen-deficient mice showed a consistent and significant reduction
in the number of surface pulmonary metastases. This indicates that
initial establishment of metastatic foci, but not tumor growth itself,
was impaired in fibrinogen-deficient mice. In contrast, plasminogen
deficiency had no effect on the number of surface pulmonary metastases
for either type of tumor, indicating that plasmin-mediated fibrinolysis
was not an important factor. Microscopic analysis of lung tissue from
tumor-bearing fibrinogen-deficient mice failed to reveal any
differences from control mice in terms of tumor stroma and
angiogenesis, thus suggesting that fibrinogen is not required in this
system for these processes. In addition, the presence of fibrinogen
deficiency did not affect the initial arrest of
125I-deoxyuridine-labeled tumor cells in the lungs, but
sustained tumor cell adherence was markedly impaired.
Hirudin, the thrombin inhibitor, has previously been shown to inhibit
the metastases of circulating tumor cells, but it is not known whether
this activity is solely related to its substrate, fibrinogen. As
expected, hirudin administration to normal mice diminished the number
of pulmonary metastatic foci by more than 20-fold compared to
saline-treated controls. Hirudin administration to fibrinogen-deficient
mice also resulted in a significant reduction compared to saline
controls, and the level was reduced to nearly zero. Thus, there is at
least one fibrinogen-independent mechanism by which hirudin exerts its
effect on tumor cell spread, and the effect is not related to direct
inhibition of cultured tumor cells.
These studies nicely demonstrate that fibrinogen plays an important
role in the pathophysiology of cancer and that it is at the least a
major determinant of the metastatic potential of tumors. It appears to
facilitate the establishment of metastases by enhancing the sustained
adherence of tumor cell emboli in the vasculature of target organs.
Tumor cell-associated thrombin generation and local conversion of
fibrinogen to fibrin may also be related to metastatic potential, but
there is at least one fibrinogen-independent mechanism for
thrombin-mediated promotion of tumor metastases. These studies have
answered important questions concerning the role of fibrinogen in tumor
spread, but other important questions remain unresolved:
1. How does fibrin(ogen) sustain tumor cell adhesion and survival?
2. What is the fibrinogen-independent mechanism by which thrombin
promotes tumor metastases?
3. What is the relative importance of soluble fibrinogen, insoluble
fibrin, and fibrin(ogen) degradation products in tumor progression?
4. What is the effect of the absence of a fibrin matrix in
tumor-bearing fibrinogen-deficient mice on spontaneous tumor metastases?
It seems likely that further experimentation using this transgenic
system will provide useful answers to these questions.
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