Relationship Between Blood Fibrinogen Concentration and Pathological Features of Cancer Patients: A 139-case Clinical Study

Angiogenesis and coagulation are among the most consistent host responses to the presence of a malignant tissue. Pathological angiogenesis and coagulation are often occurred in patients with solid tumors, especially in the occurrence of neoplasm metastasis and as targets for anti-metastatic drugs such as antiangiogenesis agents, coagulation-mediated agents and anticancer drugs. Since fibrinogen (Fib) is the most abundant and key haemostatic protein taking part in angiogenesis and coagulation, its biological and pathophysiological roles in cancer patients are intriguing. To continue foundational and translational research on Fib-related cancer pathogenesis, a phase II survey of 139 patients was carried out at the Central Hospital of Jing-An district and Shanghai University, Shanghai, China. The mean BFC of the cancer patients in this survey was overall about 35-50% greater than that in the normal population. This study showed that the mean BFC was higher in patients with long-distance metastases (N1M1 patients) than in patients with no sign of long-distance metastases (N0M0 patients). Mean BFCs were 4.42 g/L (n= 21) in patients with lung cancer, 4.36 g/L, and in patients with hepatic cancer (n=5), and 4.63 g/L in patients with stomach cancer (n=8), all higher than the average value of the cancer patients overall (4.16 g/L). However, patients with bowel and colon cancers 3.79 g/L (n=16) showed lower than them. BFC levels increased with increasing cancer duration (latency > 1 year). There was a slight decrease in BFC after one or two treatment cycles, but a more marked decrease after surgery. We propose that the BFC level in cancer patients may be influenced by and related to many aspects of cancer progression such as metastatic conditions, tumor origins, patient’s pathological stage and disease latency. As an important first-hand pathologic-therapeutics relationship study, it provides evidence for the potentiality of a new approach of Fib-targeted as individualized cancer chemotherapy and decides the stages such therapeutics may be best applied.


INTRODUCTION
Fibrinogen (Fib), a major clotting component of the blood, plays key role in the coagulation system and angiogenesis in tumors 1-2 . Fib imbalance is associated not only with coagulation malfunctions, which complicate coronary disorders and obesity, but also with some equally fatal diseases such as solid tumors and tumor metastases [3][4][5][6] . Systematic modification of Fib overproduction by anticoagulants and fibrinolytics was attempted some time ago [7][8][9] and has recently been renewed to normal anticancer drugs [9][10][11] . During the past decade, molecular and genetic investigations have further revealed the key roles of Fib in cancer develop and possible mechanisms of action: for instance, Fib-knockout mice showed greatly reduced tumor metastasis while the primary tumors were unaffected 12 , and some over-expression of Fib fragments has been demonstrated in mammary tumor cells in vitro 13 . These laboratory studies suggest that tumor cells also participate in Fib-related pathways and that Fib might be a potential therapeutic target. If this hypothesis is correct, studies of the basis of altered blood Fib concentrations (BFC) in cancer patients might be useful information of this kind more relevant than other general pathological information of human. Therefore, clinical BFC data from 139 cancer patients have been collected to offer a new insight to this hypothesis and stimulate further research of Fib-related pathogenesis and therapeutics.

MATERIALS AND METHODS
One hundred and thirty nine adult cancer inpatients (aged 22-82 years), enrolled in the Central Hospital of Jing-An District, Shanghai, China, were included in this survey. We received and enrolled patients according to the worldwide procedures of the Helsinki Agreements. The pathological characteristics of the patients were assessed by appropriate WHO classification protocols for clinico-pathological status ( Table 1). Blood fibrinogen concentration (BFC) was determined for all patients both before and after one or two treatment regimens. Major treatments included surgery, chemotherapy and thermo-therapy, separately or in combination. The mean age of the male patients in this survey was 57.34 years (median 64 years) and the mean age of the female patients was 57.2 years (median 58.5 years). BFC was determined by a routine hospital protocol. Blood (1.8ml) was anticoagulated with sodium citrate (3.8%, 0.2ml). Mixed plasma was then taken to determine BFC using a STAGO Compact biochemical detector, manufactured in China.
Cancer patients tested both before and after chemotherapy, thermo-therapy or surgery showed a slight decrease in BFC, from 3.97(95% CI 1.67~6.27)g/L to 3.61 (95% CI 1.65~5.57) g/L (n=37). A persistent increase of BFC in patients treated by non-surgical therapy was observed, from 3.11(1.11~5.11) to 4.69(2.25~7.13) g/L (n=17). Patients whose tumors had been removed by operation showed a dramatic decrease in mean BFC (from 4.70(95% CI 2.46~6.94) to 3.23(95% CI 1.23~5.23) g/L, n=20; (Table 7). However, their BFC increased again with increasing time after surgery. For example, a woman patient with an initial BFC value of 3.8 g/L showed a reduction to 2.17 g/L in the second test, 2 weeks after surgery, and a subsequent increase to 3.61 g/L at the third test.
We observed a difference in BFC as cancer latency increased. In patients with cancers of 0.5 to 1 years duration the value was 3.94(95% CI 1.32~6.56) g/L; it was 4.15(95% CI 1.39~6.91) for 1 to 2 years, and highest in later stage patients (who survived longer than 2 years), 4.26(95% CI 1.24~7.28) g/L (Table 8). Patients in the acute stage (diagnosed less than half a year previously) showed the highest BFC 4.51(95% CI 1.43~7.59) g/L. All these data show that the level of BFC in cancer patients is linked to both primary tumor growth and long-distance metastases.

DISCUSSION
Fib and endothelial cells are accumulated and malformed in solid tumor stroma nourishing and supporting tumor tissue to further enlargement, which are controlled and regulated by the interplaying of coagulation enzymes and angiogenesis factors [14][15] . Methods for disrupting these pathological processes could have great clinical significance [6][7][8][9][10][11] . Nowadays, present cancer chemotherapy is largely depending on empirical rather than well-targeted therapeutic. This often results losing the best opportunity of treatment in      patients in both rapidity and correctness 16 . An improved individualized cancer therapy has been sought out by measurement of pathological profile of patients and other approaches 16 . BFC can be an indicator for launching more powerful individualized cancer chemotherapy. Since these pathological processes are highly complicated and currently not been fully understood, we need much more experiments to focusing and pinpointing them. BFC, as a key initiator of these multi-stage processes, was extensively measured in this study, especially observation of its level in different stages of tumor-related pathogenesis. , especially if the use is in long-term 3 . Genetic investigation during the past decade suggests that tumor cells and metastases may arise from tumor Fib over-expression or assembly [12][13] . Given this information, we can determine the pharmacological mechanisms of anticancer drugs at each step and validate them clinically. Along with this investigation and previous data, we suggest a new individualized system for targeting tumor-Fib pathways may be applicable. Targeting these critical Fib-related steps with a new system of chemotherapy may confer beneficial effects, especially in combination with other chemotherapeutic regimens. Now anticancer drugs can also be selected as targeted therapy 11 . These data suggest that Fib levels can be valuable indicators of drug choices. To conclude, BFC can be a marker for choice targeted treatment and foresee the genetic status of tumor malignancy-as useful plasma data for selecting individualized cancer chemotherapy.
List of abbreviations used: Fib, fibrinogen; BFC, blood fibrinogen concentration