Histogenesis Of Malignant Fibrous Histiocytoma Research Articles

Rat malignant fibrous histiocytoma (MFH)-derived cloned cell lines (MT-8 and MT-9) show different differentiation in mesenchymal stem cell lineage

Malignant fibrous histiocytomas (MFHs) show a storiform growth pattern consisting of fibroblastic, histiocytic and undifferentiated mesenchymal cells with possible multipotency. Because MFH-like tumors are induced experimentally by some chemicals and materials, it is important to know the histogenesis of MFHs. We analyzed in vitro and in vivo characteristics of two cloned cell lines (MT-8 and MT-9) established from a spontaneous MFH found in an aged F344 rat. MT-8 and MT-9 cultured cells and their tumors induced in syngeneic rats by injection were investigated morphologically, and their tumors were evaluated by immunohistochemistry. Gene expression profiles of their cultures and induced tumors were analyzed by the comprehensive gene analysis. MT-8 cells had less developed organelles and the induced tumors represented histological characteristics of undifferentiated sarcoma (sarcoma not otherwise specified (NOS)), whereas MT-9 cells had relatively well-developed intracytoplasmic organelles such as endoplasmic reticulum, mitochondria and lysosomes and the tumors showed a storiform growth pattern typical of MFHs. MT-8 and MT-9 tumors were immuno-positive for vimentin, and the reactivity for stem cell markers (nestin, CD90, CD34, and A3) appeared to be greater in MT-9 tumor cells, and their tumor cells did not react to markers for well-differentiated cells of epithelial, myogenic and neurogenic tissues except for faint reaction for S-100 protein in MT-9 tumors. The gene analyses revealed that genes relating to “cell differentiation” were more activated in MT-9 than MT-8 tumors, whereas those involved in “cell cycle” were greater in MT-8 than MT-9 tumors. In MT-8 and MT-9, additionally, genes involved in “cell differentiation” were much greater in their tumors than in their cultures. These findings indicate that MT-8 cells are poorly differentiated mesenchymal stem cells which induce sarcomas NOS, whereas MT-9 cells, which can develop typical MFHs, have more differentiated stem cell nature with greater multipotential differentiation. In MFHs, collectively, MT-8 and MT-9 cells are regarded as “tumor stem cells” and “tumor precursors” in the stem cell lineage, respectively, according to the concept of “cancer stem cell theory”.

Recurrent intracranial myxofibrosarcoma presenting as an extensive fronto-parieto-occipital SOL: An unusual sarcoma of meningeal origin

The histogenesis of malignant fibrous histiocytoma (MFH) has een a matter of considerable debate through decades, and recent oncept does not favor a histiocytic origin as proposed initially. he storiform-pleomorphic variant is now rather a morphologic attern, encountered in many undifferentiated or dedifferentiated umors of mesenchymal or non-mesenchymal origin. The diagosis of MFH is hence reserved for tumors in which no specific ine of differentiation can be ascertained on generous sampling, upplemented by immunohistochemical panel and/or electron icroscopy [1,2]. Myxoid MFH, having a relatively better prognosis, as been designated as ‘myxofibrosarcoma’ with inclusion under he ‘myofibroblastic’ category [1,2]. We herein describe a case of ecurrent myxofibrosarcoma in a 21 year old female, presenting s an extensive fronto-parieto-occipital lesion of meningeal oriin, which to the best of our knowledge, is the second intracranial yxofibrosarcoma to be documented in literature.

P10: Osteogenic potential of cisplatin-resistant rat malignant fibrous histiocytoma (MFH)-derived cell lines

Histogenesis of malignant fibrous histiocytoma (MFH) remains elusive. To investigate cellular characteristics, we derived cisplatin-resistant MFH cell lines (MT-PR and MT-10R) from MT-P and MT-10, respectively, and compared them with MT-10, a non-cisplatin-resistant MFH line (MT-10 was isolated as a clone cell line from MT-P, and MT-P was originally established from a rat spontaneous MFH). Immunohistochemically, MT-10 reacted to vimentin, alpha-smooth muscle actin (a marker of myofibroblasts), ED1/ED2 (rat macrophage/histiocyte-specific antibodies), and A3 (rat MFH-specific antibody) in varying degrees, indicating that MFH cells have features of both fibroblasts and histiocytes. However, MT-10R and MT-PR reduced ED1-positive cell numbers. MT-10 developed tumors of a storiform pattern, while MT-10R and MT-PR tumors comprise round or polygonal cells arranged in a compact sheet including ossifying areas. MT-10R and MT-PR, and their tumors showed a reaction to alkaline phosphatase (ALP), a marker of osteoblasts. RT-PCR revealed that mRNAs of bone morphogenetic protein (BMP)-2, BMP-6 and osteopontin were significantly increased in MT-10R and MT-PR tumors. Neoplastic cells in these tumors were immunoreactive to BMP-2 and BMP-6, while MT-10 tumors were not. Cisplatin-resistant MFH cells had potential to differentiate into osteogenic tissues by producing osteogenic factors, suggesting that MFH histology may be altered under anti-cancer drug treatments. Recently, cancer differentiation-based therapy that could be induced by anti-cancer drugs, has been implied. MT-10R and MT-PR become useful experimental systems for studies on cellular differentiation provoked by anti-cancer drugs.

Potential osteogenic differentiation of cisplatin-resistant rat malignant fibrous histiocytoma-derived cell lines

Histological modulations in tumor cells treated with anti-cancer drugs have been reported. The histogenesis of malignant fibrous histiocytoma (MFH) remains elusive. To investigate cellular characteristics and alterations, therefore, we derived cisplatin-resistant MFH cell lines (MT-PR and MT-10R) from MT-P and MT-10, respectively, and compared them with MT-10, a non-cisplatin-resistant MFH line (MT-10 was isolated as a clone cell line from MT-P, and MT-P was originally established from a rat spontaneous MFH). Immunohistochemically, MT-10 reacted to vimentin, α-smooth muscle actin (a marker of myofibroblasts), ED1/ED2 (rat macrophage/histiocyte-specific antibodies), and A3 (rat MFH-specific antibody) in varying degrees, indicating that MFH cells have features of both fibroblasts and histiocytes. However, MT-10R and MT-PR reduced ED1-positive cell numbers. MT-10 developed tumors of a storiform pattern, while MT-10R and MT-PR tumors comprise round or polygonal cells arranged in a compact sheet. Additionally, MT-PR tumors included ossifying areas. MT-10R and MT-PR, and their tumors showed a reaction to alkaline phosphatase (ALP), a marker of osteoblasts. RT-PCR revealed that mRNAs of bone morphogenetic protein (BMP)-2, BMP-6 and osteopontin were significantly increased in MT-10R and MT-PR tumors. Neoplastic cells in these tumors were immunoreactive to BMP-2 and BMP-6, while MT-10 tumors were not. Cisplatin-resistant MFH cells had potential to differentiate into osteogenic tissues by producing osteogenic factors, suggesting that MFH histology may be altered under anti-cancer drug treatments. Recently, cancer differentiation-based therapy, that could be induced by anti-cancer drugs, has been implied. MT-10R and MT-PR become useful experimental systems for studies on cellular differentiation provoked by anti-cancer drugs.

Distribution of Cells Labelled by a Monoclonal Antibody (A3) against a Cloned Cell Line derived from a Rat Malignant Fibrous Histiocytoma

To pursue the histogenesis of malignant fibrous histiocytoma (MFH), of which the cell of origin is still debated, a monoclonal antibody (A3) was produced against a rat MFH-derived cloned cell line (MT-8). Antigen recognized by A3 was around 80 kDa in molecular weight and was seen on the cytoplasmic membrane of MT-8 cells by immunoelectron microscopy. A3 reacted specifically with MT-8 cells, with another rat MFH-derived cell line (MT-9) and with their induced tumours in syngeneic rats, but not with other rat tumours such as fibrosarcoma, histiocytic sarcoma, malignant meningioma, uterine leiomyosarcoma, endometrial stromal sarcoma, mononuclear cell leukaemia and malignant schwannoma. These findings indicate that A3 has a high specificity for rat MFH cells. In fetuses on gestation days 15, 18 and 20 and in postnatal rats aged 1, 4 and 8 days, A3 reacted with primitive mesenchymal cells in visceral organs and around arteries and bronchi, as well as in the lamina propria of intestinal mucosa, renal interstitium, meninges and perineurium. There were no A3-positive connective tissue cells in organs or other sites in adult rats more than 10 weeks old. It is therefore likely that MFH cells share antigens with primitive mesenchymal cells, which may be multipotent for mesenchymal differentiation. The present study suggests that MFH consists of a population of primitive, undifferentiated mesenchymal cells. A3 also immunolabelled endothelial cells of arteries, venules and pulmonary capillaries in fetal, postnatal and adult rats; vascular endothelial cells in chemically induced hepatic and renal lesions also reacted strongly with A3. However, the significance of endothelial immunoreactivity with A3 remains to be elucidated.

Metamorphosed fibroblasts and their relation to the histogenesis of malignant fibrous histiocytoma in experimental murine model.

Malignant fibrous histiocytoma (MFH) is a clinicopathologically established entity, but its histogenesis remains to be clarified. We have reported the existence of a specific cell type, the "fibrohistiocytoid (FH) cells", in various chronic inflammatory tissues. The FH cells are the metamorphosed fibroblasts and we have revealed the morphological resemblance between FH cells and MFH cells. In the present study we carried out some experiments to ascertain whether the FH cells have a possibility of neoplastic potential for the development of MFH in mice. A total of 50 female Balb/c mice treated with a chemical carcinogen, 9,10 dimethyl-1,2-benzanthracene (DMBA), were examined histopathologically from 8 to 22 weeks after the initial treatment. It was found that 1) the chemically induced tumors in the mice resembled human pleomorphic/ storiform variant of MFH and cells from the tumor were transplantable subcutaneously in the back of another mouse, 2) the tumors were composed mainly of malignant FH cells, and there were many benign FH cells and fibroblasts in granulation tissues obtained at the initial stage of the experiment, 3) all DNA histograms obtained from MFHs were aneuploid and granulation tissues were diploid, and 4) benign FH cells in the granulation tissue appeared to have higher DNA synthesis activity than typical fibroblasts on the basis of bromodeoxyuridine (BrdU) labeling and cytofluorometric studies. From these findings, we suggest that the FH cells are not only a merely morphologically changed fibroblast, but also a biologically ominous cell which may contribute to develop MFH in mice.

Phenotypic modulation in cisplatin-resistant cloned cells derived from transplantable rat malignant fibrous histiocytoma.

The histogenesis of malignant fibrous histiocytoma (MFH) was studied using cisplatin (CDDP)-resistant MT-R8 and MT-R9 cells derived from cloned undifferentiated MT-8 and fibrohistiocytic MT-9 cells, respectively, which had been established from transplantable rat MFH. CDDP concentrations required for 50% suppression of proliferation of MT-R8 and MT-R9 cells were 5.4- and 3.3-fold greater than those of parental MT-8 and MT-9, respectively. MT-R8 and MT-R9 showed the higher positive rates to histiocytic lysosomal/ antigenic (ED1 and ED2) markers. The number of alpha-smooth muscle actin (SMA)-positive cells significantly increased in MT-R8; SMA-positive cells were also observed in MT-R9, but no difference was seen between MT-9 and MT-R9. MT-R8 and MT-R9 expressed both histiocytic and myofibroblastic phenotypes. However, the histology of subcutaneous tumors induced in syngeneic rats by MT-R8 and MR-R9 did not always reflect their in vitro nature. MT-R8 developed undifferentiated sarcomas similar to parental MT-8 tumors. In contrast, MT-R9 induced tumors with polytypic histologies such as the storiform growth pattern, neoplastic growth of granular cells and myofibroblasts, osteosarcoma-like areas, collagen-rich areas containing well-developed fibroblasts and areas involving many lipoblasts. These in vivo observations suggest the multidirectional differentiation of MT-R9 cells. Phenotypic modulation of rat MFH cells seemed to be easily induced by CDDP. A possible histogenesis of MFH was discussed based on the data collected.

Enhancement of lipid phagocytosis by cloned cells derived from rat malignant fibrous histiocytoma under hyperlipemic conditions.

The histogenesis of malignant fibrous histiocytoma (MFH) was studied by observing the influence of hyperlipemic (HL) conditions on the behavior of cloned MT-8 cells with an undifferentiated mesenchymal character and MT-9 cells with histiocytic and fibroblastic features, both derived from a spontaneous rat MFH. The cells were grown in medium containing 10% normal rat serum (CSM) or 10% HL rat serum (HSM) for 1, 3, 8 and 24 h. The cells grown in HSM showed a time-dependent, significant increase in numbers of cytoplasmic lipid droplets per cell and cells positive for acid phosphatase (ACP) and non-specific esterase (NSE) compared with cells grown in CSM. The number of cells positive for two different anti-rat monocyte/macrophage monoclonal antibodies (ED-1 and ED-2) also increased significantly in HSM. This histiocytic nature was confirmed by electron microscopy. Tumors were induced by inoculating MT-8 and MT-9 cells into rats on a standard diet and rats on a HL diet. MT-8 and MT-9 tumor cells in HL rats phagocytized lipid droplets and showed stronger positive reactions for ACP and NSE compared with tumors in control rats. These results imply that xanthomatous cells in MFH may be a phenotype of MFH cells expressing an enhanced histiocytic nature. MFH cells seem to alter their behavior depending on cultural or microenvironmental conditions.

Malignant Fibrous Histiocytoma and Macrophage Differentiation.

Malignant fibrous histiocytoma (MFH) is the most common soft tissue sarcoma of adult life. Its clinicopathological entity, however, is not completely established because of its uncertain histogenesis. In this review, the histogenesis of MFH is discussed through an overview of the concept of macrophage ontogeny. Our recent multiparametric studies indicate that MFH is a tumor of mesenchymal cells with fibroblastic differentiation. Histiocyte-like cells in the tumor are considered to be not neoplastic component but infiltrated macrophages. Because this tumor is not one of the histocytes or macrophages, the term “malignant fibrous histiocytoma” is inappropriate. Instead, this tumor should be renamed as a special type of mesenchymal cell tumor differentiating toward fibroblasts and producing monocyte chemoattractants and macrophage differentiation factors.

Malignant fibrous histiocytoma. A tumor of facultative histiocytes showing mesenchymal differentiation in cultured cell lines

The histogenesis of malignant fibrous histiocytoma (MFH) is controversial. To elucidate the cellular origin and characteristics of this neoplasm, the authors analyzed cell lines grown from 17 patients (15 soft tissue MFH and 2 bone MFH) by using light and electron microscopy, immunocytochemistry, enzyme cytochemistry, and functional tests for receptors for the Fc portion of immunoglobulin (Fc receptors) and immunophagocytosis. Each culture exhibited a storiform/pleomorphic pattern with mixed cellular populations consisting of spindle cells, polygonal cells, and bizarre giant cells; these morphologic features corresponded to the histologic characteristics of the primary tumors. The cells in each MFH line displayed histiocytic functional markers such as lysosomal enzymes, Fc receptors and immunophagocytosis. However, these cells differed from monocyte-derived macrophages (histiocytes) in immunoreactivity; the MFH cells expressed a mesenchymal antigen (FU3) distributed among perivascular cells and fibroblasts but demonstrated no positive reactions with Leu-M1 (CD15) and Leu-M3 (CD14), which recognize the cells of the monocyte-macrophage lineage. In conclusion, these findings suggest that MFH is not a tumor of true histiocytes but of facultative histiocytes showing mesenchymal differentiation in vitro. Chromosomal analysis performed in one MFH line demonstrated abnormal karyotypes; the modal chromosome number was 58, with 5 marker chromosomes.

Heterogeneity of Cloned Cell Lines Established from a Transplantable Rat Malignant Fibrous Histiocytoma

Four cloned cell lines, MT‐7, MT‐8, MT‐9 and MX‐10, were established from a transplantable malignant fibrous histiocytoma (MFH) of F344 rats to investigate the histogenesis of the tumor. Cells of MT‐7, MT‐9 and MT‐10 had fine structures characteristic of histiocytes, such as numerous cell processes, many lysosomes and well‐developed cytoplasmic organelles. They stained positively for histiocytic lysosomal and antigenic markers. In addition, MT‐9 cells contained microfllaments and well‐developed RER in their cytoplasm, suggesting that they may be facultative fibroblasts. MT‐8 cells stained weakly for histiocytic markers and had scant cytoplasmic organelles. They were identified as undifferentiated mesenchymal cells. The tumors induced in syngeneic rats by inoculating MT‐7 or MT‐10 consisted of a mixture of the pleomorphic, myxoid and storiform types of MFH, and those by MT‐9 were of the storiform type. Cells forming these tumors stained positively for histiocytic markers. Tumors induced by MT‐8 consisted of undifferentiated cells negative to these stainings. The histogenesis of MFH is surmised to be related to various differentiation stages shifting from undifferentiated cells to histiocytic cells capable of acting as facultative fibroblasts.