Ishii, G. et al. Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction. Biochem. Biophys. Res. Commun. 309, 232-240
ABSTRACT To confirm whether human cancer-induced stromal cells are derived from bone marrow, bone marrow (BM) cells obtained from beta-galactosidase transgenic and recombination activating gene 1 (RAG-1) deficient double-mutant mice (H-2b) were transplanted into sublethally irradiated severe combined immunodeficient (SCID) mice (H-2d). The human pancreatic cancer cell line Capan-1 was subcutaneously xenotransplanted into SCID recipients and stromal formation was analyzed on day 14 and on day 28. Immunohistochemical and immunofluorescence studies revealed that BM-derived endothelial cells (X-gal/CD31 or H-2b/CD31 double-positive cells) and myofibroblasts (X-gal/alpha-smooth muscle actin or H-2b/alpha-smooth muscle actin double-positive cells) were present within and around the cancer nests. On day 14, the frequencies of BM-derived endothelial cells and BM-derived myofibroblasts were 25.3+/-4.4% and 12.7+/-9.6%, respectively. On day 28, the frequency of BM-derived endothelial cells was 26.7+/-9.7%, which was similar to the value on day 14. However, the frequency of BM-derived myofibroblasts was significantly higher (39.8+/-17.1%) on day 28 than on day 14 (P<0.05). The topoisomerase IIalpha-positive ratio was 2.2+/-1.2% for the H-2b-positive myofibroblasts, as opposed to only 0.3+/-0.4% for the H-2b-negative myofibroblasts, significant proliferative activity was observed in the BM-derived myofibroblasts (P<0.05). Our results indicate that BM-derived myofibroblasts become a major component of cancer-induced stromal cells in the later stage of tumor development.
- SourceAvailable from: Fatima Mechta-Grigoriou
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- "Although some data indicate that the stromal compartment, when microdissected from human breast tumors, exhibits genetic alterations, the proportion of such alterations in fibroblasts remains rare suggesting that EMT cannot be the main origin for myofibroblasts . Recent data from human breast cancers and animal models established that myofibroblasts can derive from bone marrow derived cells, such as fibrocytes or mesenchymal stem cells      . Moreover , various mesenchymal cell types, including endothelial cells, pericytes or pre-adipocytes can also be converted into myofibroblasts in breast carcinomas   . "
ABSTRACT: Compelling evidence show that Reactive Oxygen Species (ROS) levels are finely regulated in the cell and can act as "second messengers" in response to diverse stimuli. In tumor epithelial cells, ROS accumulate abnormally and induce signaling cascades that mediate the oncogenic phenotype. In addition to their impact on tumor epithelial cells, ROS also affect the surrounding cells that constitute the tumor microenvironment. Indeed, ROS production increases tumor angiogenesis, drives the onset of inflammation and promotes conversion of fibroblast into myofibroblasts. These cells, initially identified upon wound healing, exhibit similar properties to those observed in fibroblasts associated with aggressive adenocarcinomas. Indeed, analyses of tumors with distinct severity revealed the existence of multiple distinct co-existing subtypes of Carcinoma-Associated Fibroblasts (CAFs), with specific marker protein profiling. Chronic oxidative stress deeply modifies the proportion of these different fibroblast subtypes, further supporting tumor growth and metastatic dissemination. At last, ROS have been implicated in the metabolic reprogramming of both cancer cells and CAFs, allowing an adaptation to oxidative stress that ultimately promotes tumorigenesis and chemoresistance. In this review, we discuss the role of ROS in cancer cells and CAFs and their impact on tumor initiation, progression and metastasis.Seminars in Cancer Biology 01/2014; 25. DOI:10.1016/j.semcancer.2013.12.007 · 9.33 Impact Factor
Breast Cancer - Focusing Tumor Microenvironment, Stem cells and Metastasis, 12/2011; , ISBN: 978-953-307-766-6
- "Many studies demonstrated that MSCs are attracted by tumors. In one study, the bone marrow of a mouse was replaced by the bone marrow from a transgenic mouse that expressed beta-galactosidase and MSC migration monitored from the bone marrow towards a prostate tumor xenograft (Ishii et al., 2003). It was found that X-gal positive MSCs colonized the tumor and differentiated to fibroblasts and endothelial cells. "
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- "Besides originating from normal fibroblast, CAFs might also differentiate from recruited bone marrow-derived mesenchymal stem cells . In addition to fibroblasts, endothelial cells and infiltrated leukocytes may also participate in tumor progression by modulating their receptor expression profile and by releasing factors that in turn modulate leukocyte infiltration, angiogenesis and tumor growth  . "
ABSTRACT: Cancer is a life-threatening disease world-wide and colorectal cancer is the second common cause of cancer mortality. The interaction between tumor cells and stromal cells plays a crucial role in tumor initiation and progression and is partially mediated by chemokines. Chemokines predominantly participate in the chemoattraction of leukocytes to inflammatory sites. Nowadays, it is clear that CXC chemokines and their receptors (CXCR) may also modulate tumor behavior by several important mechanisms: regulation of angiogenesis, activation of a tumor-specific immune response by attracting leukocytes, stimulation of tumor cell proliferation and metastasis. Here, we review the expression and complex roles of CXC chemokines (CXCL1 to CXCL16) and their receptors (CXCR1 to CXCR6) in colorectal cancer. Overall, increased expression levels of CXC chemokines correlate with poor prognosis.Cytokine & growth factor reviews 10/2011; 22(5-6):345-58. DOI:10.1016/j.cytogfr.2011.09.002 · 6.54 Impact Factor