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Immunolocalization of MMP9 and MMP2 in osteolytic metastasis originating from MDA-MB-231 human breast cancer cells.

Liu B, Cui J, Sun J, Li J, Han X, Guo J, Yi M, Amizuka N, Xu X, Li M - Mol Med Rep (2016)

Bottom Line: Numerous tartrate-resistant acid phosphatase-positive osteoclasts were found in the metastasized lesions.The invaded tumor cells positive for mammaglobin 1 exhibited different proliferation activities and apoptosis between the metaphysis and diaphysis.Of note, MMP9 was expressed predominantly in the proliferating cell nuclear antigen‑positive area, whereas the expression of MMP2 was observed predominantly in the diaphysis, which had more TUNEL‑positive cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Bone Metabolism, School of Stomatology, Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, Shandong 250012, P.R. China.

ABSTRACT
The aim of the present study was to investigate the expression of matrix metalloproteinase (MMP)9 and MMP2, and their potential roles in bone metastasis nests using a well-standardized model of breast cancer bone metastasis in nude mice. BALB/c nu/nu mice (5-week-old; n=10) were subjected to intracardiac injection of MDA-MB-231 human breast cancer cells. After 4 weeks, the mice exhibiting radiolucent lesions in tibiae were sacrificed, and the tibiae were removed for histochemical analysis. The gene expression of MMP2 and MMP9 in the tumor cells, metaphysis and diaphysis of normal BALB/c nu/nu mice were determined using reverse transcription-polymerase chain reaction analysis. The metastatic tumor tissue occupied almost the entire bone marrow cavity. Numerous tartrate-resistant acid phosphatase-positive osteoclasts were found in the metastasized lesions. The invaded tumor cells positive for mammaglobin 1 exhibited different proliferation activities and apoptosis between the metaphysis and diaphysis. Proliferating cell nuclear antigen was expressed at high levels in the metaphyseal area, whereas TdT-mediated dUTP nick-end labeling (TUNEL)-positive cells were more evident in the diaphysis area. Of note, MMP9 was expressed predominantly in the proliferating cell nuclear antigen‑positive area, whereas the expression of MMP2 was observed predominantly in the diaphysis, which had more TUNEL‑positive cells. Taken together, the results suggested that MMP9 and MMP2 may have their own importance in extracellular matrix degradation and trabecular bone damage in different zones of bone metastasis, including the metaphysis and diaphysis.

No MeSH data available.


Related in: MedlinePlus

Schematic model showing the distribution and functions of MMP9 and MMP2 in tumor cell proliferation and colonization within the osseous microenvironment. (A and B) Following colonization in the metaphyseal microenvironment, the tumor cells exhibited a high level of MMP9 production, with dynamic proliferation activity. As tumor cells migrated to the diaphysis, the tumor derived expression of MMP9 decreased, whereas an increase in the expression of MMP2 was detected. However, this process was accompanied by a wave of tumor cell apoptosis. Tumor derived MMPs and host-derived MMPs further initiated bone matrix degradation. MMP, matrix metalloproteinase.
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f5-mmr-14-02-1099: Schematic model showing the distribution and functions of MMP9 and MMP2 in tumor cell proliferation and colonization within the osseous microenvironment. (A and B) Following colonization in the metaphyseal microenvironment, the tumor cells exhibited a high level of MMP9 production, with dynamic proliferation activity. As tumor cells migrated to the diaphysis, the tumor derived expression of MMP9 decreased, whereas an increase in the expression of MMP2 was detected. However, this process was accompanied by a wave of tumor cell apoptosis. Tumor derived MMPs and host-derived MMPs further initiated bone matrix degradation. MMP, matrix metalloproteinase.

Mentions: Metaphysis is the most common homing site for tumor cells due to its high level of vascularization. Once tumor cells home to metaphysis, they are stimulated to proliferate by MMP9 (25) and bone-derived growth factors, including TGF-β (26), for their subsequent colonization in bone. Furthermore, Nutter et al demonstrated that the expression of MMP9 was increased on tumor cells colonization in bone (25). These findings were verified in the present study, which demonstrated that MMP9 was overexpressed in the metaphysis with a high level of PCNA-positive expression in the tumor cells (Fig. 5A). Tumor cells become the predominant source of MMP9 production with the extension of the bone metastasis nests, although MMP9 are predominantly derived from osteoclasts and vascular endothelial cells prior to tumor invasion. As shown in Fig. 5B, the 'vicious cycle', in which the original MMP9 derived from osteoclasts stimulates the proliferation of invaded tumor cells and subsequent colonization of tumor cells, accelerates the expression of MMP9 may provide a further explanation for tumor bone metastasis and offer a tumor prevention strategy. In addition, the increased MMP9 is involved in the recruitment of bone-resorbing osteoclasts, which leads to further osteolytic lesions (27,28).


Immunolocalization of MMP9 and MMP2 in osteolytic metastasis originating from MDA-MB-231 human breast cancer cells.

Liu B, Cui J, Sun J, Li J, Han X, Guo J, Yi M, Amizuka N, Xu X, Li M - Mol Med Rep (2016)

Schematic model showing the distribution and functions of MMP9 and MMP2 in tumor cell proliferation and colonization within the osseous microenvironment. (A and B) Following colonization in the metaphyseal microenvironment, the tumor cells exhibited a high level of MMP9 production, with dynamic proliferation activity. As tumor cells migrated to the diaphysis, the tumor derived expression of MMP9 decreased, whereas an increase in the expression of MMP2 was detected. However, this process was accompanied by a wave of tumor cell apoptosis. Tumor derived MMPs and host-derived MMPs further initiated bone matrix degradation. MMP, matrix metalloproteinase.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4940081&req=5

f5-mmr-14-02-1099: Schematic model showing the distribution and functions of MMP9 and MMP2 in tumor cell proliferation and colonization within the osseous microenvironment. (A and B) Following colonization in the metaphyseal microenvironment, the tumor cells exhibited a high level of MMP9 production, with dynamic proliferation activity. As tumor cells migrated to the diaphysis, the tumor derived expression of MMP9 decreased, whereas an increase in the expression of MMP2 was detected. However, this process was accompanied by a wave of tumor cell apoptosis. Tumor derived MMPs and host-derived MMPs further initiated bone matrix degradation. MMP, matrix metalloproteinase.
Mentions: Metaphysis is the most common homing site for tumor cells due to its high level of vascularization. Once tumor cells home to metaphysis, they are stimulated to proliferate by MMP9 (25) and bone-derived growth factors, including TGF-β (26), for their subsequent colonization in bone. Furthermore, Nutter et al demonstrated that the expression of MMP9 was increased on tumor cells colonization in bone (25). These findings were verified in the present study, which demonstrated that MMP9 was overexpressed in the metaphysis with a high level of PCNA-positive expression in the tumor cells (Fig. 5A). Tumor cells become the predominant source of MMP9 production with the extension of the bone metastasis nests, although MMP9 are predominantly derived from osteoclasts and vascular endothelial cells prior to tumor invasion. As shown in Fig. 5B, the 'vicious cycle', in which the original MMP9 derived from osteoclasts stimulates the proliferation of invaded tumor cells and subsequent colonization of tumor cells, accelerates the expression of MMP9 may provide a further explanation for tumor bone metastasis and offer a tumor prevention strategy. In addition, the increased MMP9 is involved in the recruitment of bone-resorbing osteoclasts, which leads to further osteolytic lesions (27,28).

Bottom Line: Numerous tartrate-resistant acid phosphatase-positive osteoclasts were found in the metastasized lesions.The invaded tumor cells positive for mammaglobin 1 exhibited different proliferation activities and apoptosis between the metaphysis and diaphysis.Of note, MMP9 was expressed predominantly in the proliferating cell nuclear antigen‑positive area, whereas the expression of MMP2 was observed predominantly in the diaphysis, which had more TUNEL‑positive cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Bone Metabolism, School of Stomatology, Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, Shandong 250012, P.R. China.

ABSTRACT
The aim of the present study was to investigate the expression of matrix metalloproteinase (MMP)9 and MMP2, and their potential roles in bone metastasis nests using a well-standardized model of breast cancer bone metastasis in nude mice. BALB/c nu/nu mice (5-week-old; n=10) were subjected to intracardiac injection of MDA-MB-231 human breast cancer cells. After 4 weeks, the mice exhibiting radiolucent lesions in tibiae were sacrificed, and the tibiae were removed for histochemical analysis. The gene expression of MMP2 and MMP9 in the tumor cells, metaphysis and diaphysis of normal BALB/c nu/nu mice were determined using reverse transcription-polymerase chain reaction analysis. The metastatic tumor tissue occupied almost the entire bone marrow cavity. Numerous tartrate-resistant acid phosphatase-positive osteoclasts were found in the metastasized lesions. The invaded tumor cells positive for mammaglobin 1 exhibited different proliferation activities and apoptosis between the metaphysis and diaphysis. Proliferating cell nuclear antigen was expressed at high levels in the metaphyseal area, whereas TdT-mediated dUTP nick-end labeling (TUNEL)-positive cells were more evident in the diaphysis area. Of note, MMP9 was expressed predominantly in the proliferating cell nuclear antigen‑positive area, whereas the expression of MMP2 was observed predominantly in the diaphysis, which had more TUNEL‑positive cells. Taken together, the results suggested that MMP9 and MMP2 may have their own importance in extracellular matrix degradation and trabecular bone damage in different zones of bone metastasis, including the metaphysis and diaphysis.

No MeSH data available.


Related in: MedlinePlus