Mast cell inhibitor cromolyn increases blood clotting and hypoxia in murine breast cancer

Abstract

Human breast cancer is extensively infiltrated by mast cells that contain powerful anticoagulants such as heparin, tryptase and chymase. To determine if human breast cancer is associated with mast cell activation, we measured the levels of mast cell tryptase (an indicator of mast cell activation) in the blood of 20 women with varying stages of breast cancer. The mean level of tryptase in women with breast cancer (10.3 ؎ 4.2 g/L) was significantly higher than in 50 normal healthy women without breast cancer (3.0 ؎ 2.5 g/L, p < 0.05 by two-tailed t-test). To explore the role of mast cells in breast cancer in more detail, we then carried out experiments that were aimed at determining if an inhibitor of mast cell function, sodium cromolyn, could increase blood clotting and hypoxia within subcutaneous implants of the 4T1 mammary adenocarcinoma cell line in mice. We treated tumor-bearing mice with 5 consecutive daily doses of sodium cromolyn (10 mg/kg, i.p.). An average of 30% of the periphery of the tumors from the 5 drug-treated mice contained large lakes of clotted blood that were not evident in any of the tumors from the control (untreated) mice. By computerized image analysis of tumors immunostained for a hypoxia marker (pimonidazole), the tumors from the treated mice had significantly more hypoxia (35 ؎12 % hypoxic regions, n ‫؍‬ 5) than the tumors from untreated (control) mice (16 ؎ 7%, n ‫؍‬ 5). We conclude that sodium cromolyn enhanced peri-tumoral blood clotting and intratumoral hypoxia. These results suggest that mast cells may play an important role in regulating blood clotting and hypoxia within breast cancer.

Serum Level of Mast Cell Tryptase in Patients with Oral Squamous Cell Carcinoma: Lack of Correlation with Clinicopathologic Factors

“…Increased MCT in level in sera of patients with breast cancer has been shown, previously (Samoszuk and Corwin, 2003), One study showed their importance as a diagnostic and prognostic marker for distinguishing pancreatic cancer from benign tumors in the same location (Strouch et al, 2010). According to the previous reports; we hypothesized that mast cell activation could be a useful parameter for evaluating OSCC patients.…”

“…MCT level in biologic fluids is used as an indicator of number and activation of mast cells (Hogan and Schwartz, 1997). This level has been determined in breast and pancreatic cancer (Samoszuk and Corwin, 2003;Strouch et al, 2010). Strouch et al have stated that mast cell accumulation in the tumoral tissue may be reflected in the serum and the serum level of tryptase may be a useful marker to distinguish malignant from benign tumors (Strouch et al, 2010).…”

“…We observed a mean of 12±14 ng/ml in the patients' sera which was only a little more than the normal range. Samozuk and Corwin have shown a mean of 10.3±2.4 in women with different stage of breast cancer, which was three times greater than normal women (Samoszuk and Corwin, 2003). Sperr et al have also demonstrated elevated level of tryptase (greater than 15 ng/ml) in 40-44% of acute myeloid leukemia (AML), but not in acute lymphocytic leukemia (ALL) patients (Sperr et al, 2001).…”

“…According to these results, some authors have considered mast cells as a target for cancer therapy (Nechushtan, 2009). Other researchers assessed the possible clinical relevance of mast cell degranulation in some malignant tumors (Samoszuk and Corwin, 2003).…”

Biological Function of Plasma Kallikrein in Mammary Gland Stromal Development and Tumor Metastasis

“…It has been demonstrated previously that inflammatory cells play an important role in both mammary gland development [11,12] and mammary tumor progression [13][14][15][16]. However, no previous work has attempted to elucidate the specific role of mast cells in mammary gland development.…”