Degranulating mast cells in fibrotic regions of human tumors and evidence that mast cell heparin interferes with the growth of tumor cells through a mechanism involving fibroblasts

BACKGROUND: The purpose of this study was to test the hypothesis that mast cells that are present in fibrotic regions of cancer can suppress the growth of tumor cells through an indirect mechanism involving peri-tumoral fibroblasts. METHODS: We first immunostained a wide variety of human cancers for the presence of degranulated mast cells. In a subsequent series of controlled in vitro experiments, we then co-cultured UACC-812 human breast cancer cells with normal fibroblasts in the presence or absence of different combinations and doses of mast cell tryptase, mast cell heparin, a lysate of the human mast cell line HMC-1, and fibroblast growth factor-7 (FGF-7), a powerful, heparin-binding growth factor for breast epithelial cells. RESULTS: Degranulating mast cells were localized predominantly in the fibrous tissue of every case of breast cancer, head and neck cancer, lung cancer, ovarian cancer, non-Hodgkin's lymphoma, and Hodgkin's disease that we examined. Mast cell tryptase and HMC-1 lysate had no significant effect on the clonogenic growth of cancer cells co-cultured with fibroblasts. By contrast, mast cell heparin at multiple doses significantly reduced the size and number of colonies of tumor cells co-cultured with fibroblasts, especially in the presence of FGF-7. Neither heparin nor FGF-7, individually or in combination, produced any significant effect on the clonogenic growth of breast cancer cells cultured without fibroblasts. CONCLUSION: Degranulating mast cells are restricted to peri-tumoral fibrous tissue, and mast cell heparin is a powerful inhibitor of clonogenic growth of tumor cells co-cultured with fibroblasts. These results may help to explain the well-known ability of heparin to inhibit the growth of primary and metastatic tumors

PPAR[delta] activation enhances skeletal muscle regeneration

Skeletal muscle relies mostly on its resident progenitor cells, the satellite cells, for postnatal growth and regeneration. Therefore, maintaining proper function and healthy population of satellite cells are critical for the ability of muscle to control damage. Endurance exercise elicits a myriad of adaptive responses in the muscle, including an increase in the satellite cell number. Targeted expression of constitutively active Peroxisome Proliferator-Activated Receptor delta (VP16-PPAR[delta]) in the skeletal muscle mimics endurance training induced fiber type remodeling, including, glycolytic to oxidative fiber type switch and concomitant increase in the running capacity. Currently, however, it is unknown whether transcriptionally directed "endurance exercise training" adaptations by PPAR[delta] in the muscle is sufficient to affect satellite cell homeostasis and function. We herein present that PPAR[delta] activation promotes acceleration of regenerative process after an acute injury. We found that the skeletal muscle specific over-expression of PPAR[delta] induces increase in the satellite cell population. Furthermore, we observed an increase in the number of proliferating cells after injury, leading to an increase in the number of nascent regenerating fibers. Gene expression analyses showed an earlier resolution of inflammatory response and induction of myogenic markers, suggesting that PPAR[delta] actuates temporal shift of the regenerative process. Interestingly, PPAR[delta] promotes myoblast proliferation immediately after the injury, which correlates with strong induction of Notch signaling pathway by PPAR[delta]. Additionally, acute pharmacological activation of PPAR[delta] also promoted efficient restoration of fiber integrity. Collectively, our results demonstrate a new role for PPAR[delta] in skeletal muscle regeneration. Our findings allude to the therapeutic potential of PPAR[delta], not only for the treatment of an acute injury, but also in Notch-dependent aging associated loss of regenerative capacity of the muscl

PPAR[delta] activation enhances skeletal muscle regeneration

Skeletal muscle relies mostly on its resident progenitor cells, the satellite cells, for postnatal growth and regeneration. Therefore, maintaining proper function and healthy population of satellite cells are critical for the ability of muscle to control damage. Endurance exercise elicits a myriad of adaptive responses in the muscle, including an increase in the satellite cell number. Targeted expression of constitutively active Peroxisome Proliferator-Activated Receptor delta (VP16-PPAR[delta]) in the skeletal muscle mimics endurance training induced fiber type remodeling, including, glycolytic to oxidative fiber type switch and concomitant increase in the running capacity. Currently, however, it is unknown whether transcriptionally directed "endurance exercise training" adaptations by PPAR[delta] in the muscle is sufficient to affect satellite cell homeostasis and function. We herein present that PPAR[delta] activation promotes acceleration of regenerative process after an acute injury. We found that the skeletal muscle specific over-expression of PPAR[delta] induces increase in the satellite cell population. Furthermore, we observed an increase in the number of proliferating cells after injury, leading to an increase in the number of nascent regenerating fibers. Gene expression analyses showed an earlier resolution of inflammatory response and induction of myogenic markers, suggesting that PPAR[delta] actuates temporal shift of the regenerative process. Interestingly, PPAR[delta] promotes myoblast proliferation immediately after the injury, which correlates with strong induction of Notch signaling pathway by PPAR[delta]. Additionally, acute pharmacological activation of PPAR[delta] also promoted efficient restoration of fiber integrity. Collectively, our results demonstrate a new role for PPAR[delta] in skeletal muscle regeneration. Our findings allude to the therapeutic potential of PPAR[delta], not only for the treatment of an acute injury, but also in Notch-dependent aging associated loss of regenerative capacity of the muscl

Degranulating mast cells in fibrotic regions of human tumors and evidence that mast cell heparin interferes with the growth of tumor cells through a mechanism involving fibroblasts

BackgroundThe purpose of this study was to test the hypothesis that mast cells that are present in fibrotic regions of cancer can suppress the growth of tumor cells through an indirect mechanism involving peri-tumoral fibroblasts.MethodsWe first immunostained a wide variety of human cancers for the presence of degranulated mast cells. In a subsequent series of controlled in vitro experiments, we then co-cultured UACC-812 human breast cancer cells with normal fibroblasts in the presence or absence of different combinations and doses of mast cell tryptase, mast cell heparin, a lysate of the human mast cell line HMC-1, and fibroblast growth factor-7 (FGF-7), a powerful, heparin-binding growth factor for breast epithelial cells.ResultsDegranulating mast cells were localized predominantly in the fibrous tissue of every case of breast cancer, head and neck cancer, lung cancer, ovarian cancer, non-Hodgkin's lymphoma, and Hodgkin's disease that we examined. Mast cell tryptase and HMC-1 lysate had no significant effect on the clonogenic growth of cancer cells co-cultured with fibroblasts. By contrast, mast cell heparin at multiple doses significantly reduced the size and number of colonies of tumor cells co-cultured with fibroblasts, especially in the presence of FGF-7. Neither heparin nor FGF-7, individually or in combination, produced any significant effect on the clonogenic growth of breast cancer cells cultured without fibroblasts.ConclusionDegranulating mast cells are restricted to peri-tumoral fibrous tissue, and mast cell heparin is a powerful inhibitor of clonogenic growth of tumor cells co-cultured with fibroblasts. These results may help to explain the well-known ability of heparin to inhibit the growth of primary and metastatic tumors

Novel SWI/SNF Chromatin-Remodeling Complexes Contain a Mixed-Lineage Leukemia Chromosomal Translocation Partner

The SWI/SNF family of chromatin-remodeling complexes has been discovered in many species and has been shown to regulate gene expression by assisting transcriptional machinery to gain access to their sites in chromatin. Several complexes of this family have been reported for humans. In this study, two additional complexes are described that belong to the same SWI/SNF family. These new complexes contain as many as eight subunits identical to those found in other SWI/SNF complexes, and they possess a similar ATP-dependent nucleosome disruption activity. But unlike known SWI/SNFs, the new complexes are low in abundance and contain an extra subunit conserved between human and yeast SWI/SNF complexes. This subunit, ENL, is a homolog of the yeast SWI/SNF subunit, ANC1/TFG3. Moreover, ENL is a fusion partner for the gene product of MLL that is a common target for chromosomal translocations in human acute leukemia. The resultant MLL-ENL fusion protein associates and cooperates with SWI/SNF complexes to activate transcription of the promoter of HoxA7, a downstream target essential for oncogenic activity of MLL-ENL. Our data suggest that human SWI/SNF complexes show considerable heterogeneity, and one or more may be involved in the etiology of leukemia by cooperating with MLL fusion proteins