Abstract. Several studies have demonstrated that colonystimulating factors (CSFs) are closely associated with tumor progression, metastasis and invasion through autocrine or paracrine mechanism in lung cancer. However, biologic roles of CSFs are still unknown. Elucidating the biologic roles of CSFs and the regulatory mechanisms of tumor-specific behavior by CSFs raises the possibility of having a new therapeutic approach for lung cancer. We previously established two adenocarcinoma cell lines, A924 and A964 and a large cell carcinoma cell line MI-4. MI-4 and A924 constitutively produced an abundant dose of granulocyte macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF). We examined the effects of GM-CSF and M-CSF on tumor growth, death, and invasion in CSF-producing (A924 and MI-4) and non-producing lung cancer cells (A549 and A964). These cell lines demonstrated both GM-CSF and M-CSF receptor mRNA expression. In our study, GM-CSF seemed to have advantage for tumor proliferation and invasion in lung cancer cells. M-CSF seemed to have advantage for tumor invasion, but not proliferation. The tumor-specific phenotypes (proliferation, invasion and survival) up-regulated by GM-CSF and M-CSF were mediated through MEK/ERK and PI3k/Akt pathways. However, when MEK/ERK was activated by transfection of active form of MEK1 cDNA, the tumor-specific behavior was promoted in CSF-non-producing cells, whereas inhibited in CSF-producing cells though MEK/ERK activation increased constitutive GM-CSF production. MEK/ERK signaling regulated differently tumor-specific behavior between CSFproducing cells and CSF-non-producing cells.
A 36-year-old womanwith positional headache was found to have primary low cerebrospinal fluid (CSF) pressure syndrome and galactorrhea. The CSFpressure at lumbar puncture was not measurable. Magnetic resonance imaging demonstrated that the ventricle and cerebral sulcus were narrowed and the pituitary stalk was oppressed by the brain. Hyperresponsiveness of prolactin was noted after stimulation with thyrotropin-releasing hormone.These abnormalities disappeared with normalization of CSFpressure with the treatment. Galactorrhea was apparently due to oppression of the pituitary stalk by downwardmovementof the brain. (Internal Medicine 32: 228-231, 1993)
We previously established two lung cancer cell lines, OKa-C-1 and MI-4, which constitutively produce abundant granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage-colony stimulating factor (GM-CSF). Inflammatory cytokines, tumor necrosis factor-alpha (TNF-α α α α) and interleukin ( ccasionally, leukocytosis is observed in patients with several cell types of carcinoma with an aggressive clinical course.
Micropapillary carcinoma has been described in various organs, including the breast, urinary bladder, ovary and lung. We here present a case of pulmonary micropapillary carcinoma in a 72-year-old Japanese man who died of respiratory failure and septic shock, following which autopsy was performed. A mass measuring 2.5 x 2.5 x 2.5 cm was observed in the left lower lobe of the lung. The tumor showed moderately differentiated papillary adenocarcinoma with a focal micropapillary component. Carcinomatous lymphangiosis was also observed in the left lung and metastatic lesions were observed in the bilateral lung, liver, vertebra, muscle layer of the urinary bladder, right adrenal gland, spleen and lymph nodes. The micropapillary component was predominant at some metastatic sites. Immunohistochemically, both the adenocarcinoma and micropapillary components were positive for cytokeratin (CK) 7, CK19, TTF (thyroid transcription factor)-1, carcinoembryonic antigen (CEA) and surfactant apoprotein A (SP-A), and negative for CK20, estrogen receptor, progesterone receptor, uroplakin III, and CA125. The invasive area of the conventional adenocarcinoma component contained a large number of myofibroblasts, whereas the stroma of the micropapillary component contained a small number of myofibroblasts. However, no myofibroblasts were observed in the stroma of the central core of the non-invasive micropapillary carcinoma. Several lymphatic invasions by neoplastic cells were identified in the peripheral area of the micropapillary component using D2-40 antibody. The immunohistochemical profile may be helpful in determining the primary location of the neoplasm containing micropapillary features. Myofibroblasts are present in the stroma of the invasive neoplastic nests in the micropapillary component as well as the conventional adenocarcinoma component, and D2-40 monoclonal antibody may be useful for evaluating the lymphatic invasion of pulmonary micropapillary carcinoma.
We previously established 2 lung cancer cell lines, OKa‐C‐1 and MI‐4, which constitutively produce an abundant dose of granulocyte‐colony stimulating factor (G‐CSF) and granulocyte macrophage‐colony stimulating factor (GM‐CSF). Many other cases with G‐CSF or GM‐CSF producing tumors have been reported up to the present. However, the biological properties of the overproduction of G‐CSF and GM‐CSF by tumor cells have not been well known. Several reports demonstrated the presence of an autocrine growth loop for G‐CSF and GM‐CSF in nonhematopoietic tumor cells. We showed that exogenous G‐CSF and GM‐CSF stimulated cell growth in a dose‐dependent manner in OKa‐C‐1 and MI‐4 cells. We could detect the presence of G‐CSF and GM‐CSF receptors in both cell lines by RT‐PCR analysis. We have previously shown that inflammatory cytokines, tumor necrosis factor (TNF)‐α and interleukin (IL)‐1β enhance the expression of G‐CSF and GM‐CSF in the cell lines. However, the factors that regulate constitutive production of G‐CSF or GM‐CSF by tumor cells are still unknown well. In our study, we first reported that serum deprivation stimulated constitutive production of G‐CSF and GM‐CSF by lung tumor cells through activation of nuclear factor (NF)‐κB and p44/42 mitogen‐activated protein kinase (MAPK) pathway signaling. We suggest that G‐CSF and GM‐CSF constitutively produced by tumor cells could grow tumor itself and rescue tumor cells from the cytotoxicity of serum deprivation. © 2004 Wiley‐Liss, Inc.
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