Ishii, G. et al. Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction. Biochem. Biophys. Res. Commun. 309, 232-240

Hannover Medical School, Hanover, Lower Saxony, Germany
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 09/2003; 309(1):232-40. DOI: 10.1016/S0006-291X(03)01544-4
Source: PubMed


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.

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    • "In the context of cancer, Quante et al. found that approximately 20% of the myofibroblasts in an inflammation-induced gastric cancer model were bone-marrow derived (29). In a pancreatic cancer model, BMCs contributed with up to 40% to the α-SMA-positive CAF population (28). However, in a breast cancer model studying systemic signaling, myofibroblasts in tumors growing at a distant site were derived from local sources but not from BMCs (25), indicating tissue type or cancer model-specific differences. "
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    ABSTRACT: Tumor- or cancer-associated fibroblasts (CAFs) are one of the most abundant stromal cell types in different carcinomas and comprise a heterogeneous cell population. Classically, CAFs are assigned with pro-tumorigenic effects stimulating tumor growth and progression. More recent studies demonstrated also tumor-inhibitory effects of CAFs suggesting that tumor-residing fibroblasts exhibit a similar degree of plasticity as other stromal cell types. Reciprocal interactions with the tumor milieu and different sources of origin are emerging as two important factors underlying CAF heterogeneity. This review highlights recent advances in our understanding of CAF biology and proposes to expand the term of cellular "polarization," previously introduced to describe different activation states of various immune cells, onto CAFs to reflect their phenotypic diversity.
    Full-text · Article · Mar 2014 · Frontiers in Oncology
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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 [57]. 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 [58] [59] [60] [61] [62] [63]. Moreover , various mesenchymal cell types, including endothelial cells, pericytes or pre-adipocytes can also be converted into myofibroblasts in breast carcinomas [56] [64] [65]. "
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    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.
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    • "While the origin of CAFs is not fully defined, they are thought to arise from several sources. Depending on the exact type of cancer, up to 40% of CAFs can be derived from bone marrow precursor cells (Ishii et al. 2003, Direkze et al. 2004) that are attracted to the site of the neoplastic growth from the circulation and populate the growing tumour. CAFs may also originate from epithelial cancer cells that have undergone epithelial-to-mesenchymal transition (Petersen et al. 2003). "
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    ABSTRACT: MicroRNAs (miRNAs) represent a class of small non-coding RNAs with an important regulatory role in various physiological processes as well as in several pathologies including cancers. Noteworthy, recent evidence suggests that the regulatory role of miRNAs during carcinogenesis is not limited to the cancer cells but they are also implicated in the activation of tumor stroma and its transition into a cancer-associated state. Results from experimental studies involving cells cultured in vitro and mice bearing experimental tumors, corroborated by profiling of clinical cancers for miRNA expression, underline this role and identify miRNAs as a potent regulator of the cross-talk between cancer and stroma cells. Considering the fundamental role of the tumor microenvironment in determining both the clinical characteristics of the disease as well as the efficacy of anticancer therapy, miRNAs emerge as an attractive target bearing important prognostic and therapeutic significance during carcinogenesis. In this article, we will review the available results that underline the role of miRNAs in tumor stroma biology and emphasize their potential value as tools for the management of the disease.
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