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PLoS ONE 01/2013; 8(3). · 4.09 Impact Factor
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ABSTRACT: To meet the requirements for rapid tumor growth, a complex array of non-neoplastic cells are recruited to the tumor microenvironment. These cells facilitate tumor development by providing matrices, cytokines, growth factors, as well as vascular networks for nutrient and waste exchange, however their precise origins remain unclear. Through multicolored tissue transplant procedures; we have quantitatively determined the contribution of bone marrow-derived and adipose-derived cells to stromal populations within syngeneic ovarian and breast murine tumors. Our results indicate that subpopulations of tumor-associated fibroblasts (TAFs) are recruited from two distinct sources. The majority of fibroblast specific protein (FSP) positive and fibroblast activation protein (FAP) positive TAFs originate from mesenchymal stem/stromal cells (MSC) located in bone marrow sources, whereas most vascular and fibrovascular stroma (pericytes, α-SMA(+) myofibroblasts, and endothelial cells) originates from neighboring adipose tissue. These results highlight the capacity for tumors to utilize multiple sources of structural cells in a systematic and discriminative manner.
PLoS ONE 01/2012; 7(2):e30563. · 4.09 Impact Factor
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ABSTRACT: The pattern of failure is one of the major causes of mortality among thoracic patients. Studies have shown a correlation between local control and dose. Intensity-modulated radiation therapy (IMRT) has resulted in conformal dose distributions while limiting dose to normal tissue. However, thoracic malignancies treated with IMRT to highly conformal doses up to 70 Gy still have been found to fail. Thus, the need for dose escalation through simultaneous integrated boost (SIB) may prove effective in minimizing reoccurrences. For our study, 28 thoracic IMRT plans were reoptimized via dose escalation to the gross tumor volume (GTV) and planning target volume (PTV) of 79.2 Gy and 68.4 Gy, respectively. Reoccurrences in surrounding regions of microscopic disease are rare therefore, dose-escalating regional nodes (outside GTV) were not included. Hence, the need to edit GTV margins was acceptable for our retrospective study. A median dose escalation of approximately 15 Gy (64.8-79.2 Gy) via IMRT using SIB was deemed achievable with minimal percent differences received by critical structures compared with the original treatment plan. The target's mean doses were significantly increased based on p-value analysis, while the normal tissue structures were not significantly changed.
Medical dosimetry: official journal of the American Association of Medical Dosimetrists 12/2010; 36(4):383-8. · 1.26 Impact Factor
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ABSTRACT: To describe six cases of unknown primary carcinoma of the retroperitoneum that were positive for human papillomavirus (HPV), a surrogate molecular marker for high-risk HPV (p16), or both.
Using the MD Anderson pathology database, females with confirmed HPV or p16 expression within retroperitoneal carcinomas of unknown primary were identified. Clinical data were collected by retrospective chart review. One pathologist reviewed all histology. Individuals with known primary were excluded. Data regarding individual demographics, presentation, Pap test history, pathology, HPV and p16 positivity, and outcome were analyzed using descriptive statistics.
Six individuals were identified. The median age of the individuals was 43.5 years (range 27-54). Three malignancies (50%) were squamous and three (50%) were undifferentiated. Median follow-up was 12 months (range 6-48 months). Two of the six (33%) individuals had remote histories (more than 10 years) of abnormal Pap test results. All had normal gynecologic examination and Pap test results at diagnosis. Four tumors were HPV-positive (66%) and six were p16-positive (100%). All samples that were HPV-positive were also p16-positive. All individuals underwent treatment with chemotherapy, radiation, or both. One individual underwent initial attempt at resection that was unsuccessful. Two individuals are without evidence of disease, two have had progression of disease, and two have died of their disease.
Pelvic masses of unknown primary may be HPV-related despite normal cervical examinations.
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Obstetrics and Gynecology 11/2010; 116(5):1042-6. · 4.73 Impact Factor
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Frank Marini,
Matus Studeny,
Jennifer Dembinski,
Keri L. Watson,
Shannon Kidd,
Erika Spaeth,
Zhizong Zeng,
Xiaoyang Ling, Ann Klopp,
Fredrick Lang,
Brett Hall,
Michael Andreeff
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ABSTRACT: Data published over the last 10 years suggest that mesenchymal stem/stromal cells (MSC) possess the innate capacity to home
to sites of inflammation, including tumors and wounding microenvironments. Evidence suggests that the increased production
of inflammatory mediators found at these sites is potential attractants for recruitment and engraftment. This innate homing
response can be exploited by using MSC as a cellular delivery vehicle to deliver anticancer agents directly to tumors. The
high-level intratumoral production of these agents controls tumor growth and prolongs survival in numerous animal models.
In this review, we examine the ability of MSC to selectively home to and engraft within the tumor microenvironment and the
multiple gene products delivered by MSC when used as delivery vehicles for anticancer therapies.
KeywordsCarcinoma-Associated Fibroblast (CAF)-Tumor Microenvironment-Tumor homing-Tumor stroma-Interferon-beta
07/2010: pages 113-139;
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ABSTRACT: Multipotent mesenchymal stromal/stem cells (MSC) have shown potential clinical utility. However, previous assess-ments of MSC behavior in recipients have relied on visual detection in host tissue following sacrifice, failing to monitor in vivo MSC dispersion in a single animal and limiting the number of variables that can be observed concurrently. In this study, we used noninvasive, in vivo bioluminescent imaging to determine conditions under which MSC selec-tively engraft in sites of inflammation. MSC modified to express firefly luciferase (ffLuc-MSC) were injected into healthy mice or mice bearing inflammatory insults, and MSC localization was followed with bioluminescent imag-ing. The inflammatory insults investigated included cutane-ous needle-stick and surgical incision wounds, as well as xenogeneic and syngeneic tumors. We also compared tumor models in which MSC were i.v. or i.p. delivered. Our results demonstrate that ffLuc-expressing human MSC (hMSC) systemically delivered to nontumor-bearing animals initially reside in the lungs, then egress to the liver and spleen, and decrease in signal over time. However, hMSC in wounded mice engraft and remain detectable only at injured sites. Similarly, in syngeneic and xenogeneic breast carcinoma-bearing mice, bioluminescent detection of systemically deliv-ered MSC revealed persistent, specific colocalization with sites of tumor development. This pattern of tropism was also observed in an ovarian tumor model in which MSC were i.p. injected. In this study, we identified conditions under which MSC tropism and selective engraftment in sites of inflamma-tion can be monitored by bioluminescent imaging over time. Importantly, these consistent findings were independent of tumor type, immunocompetence, and route of MSC deliv-ery. STEM CELLS 2009;27:2614–2623
Stem Cells 09/2009; 27(10):2614-2623. · 7.78 Impact Factor
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ABSTRACT: Multipotent mesenchymal stromal/stem cells (MSC) have shown potential clinical utility. However, previous assessments of MSC behavior in recipients have relied on visual detection in host tissue following sacrifice, failing to monitor in vivo MSC dispersion in a single animal and limiting the number of variables that can be observed concurrently. In this study, we used noninvasive, in vivo bioluminescent imaging to determine conditions under which MSC selectively engraft in sites of inflammation. MSC modified to express firefly luciferase (ffLuc-MSC) were injected into healthy mice or mice bearing inflammatory insults, and MSC localization was followed with bioluminescent imaging. The inflammatory insults investigated included cutaneous needle-stick and surgical incision wounds, as well as xenogeneic and syngeneic tumors. We also compared tumor models in which MSC were i.v. or i.p. delivered. Our results demonstrate that ffLuc-expressing human MSC (hMSC) systemically delivered to nontumor-bearing animals initially reside in the lungs, then egress to the liver and spleen, and decrease in signal over time. However, hMSC in wounded mice engraft and remain detectable only at injured sites. Similarly, in syngeneic and xenogeneic breast carcinoma-bearing mice, bioluminescent detection of systemically delivered MSC revealed persistent, specific colocalization with sites of tumor development. This pattern of tropism was also observed in an ovarian tumor model in which MSC were i.p. injected. In this study, we identified conditions under which MSC tropism and selective engraftment in sites of inflammation can be monitored by bioluminescent imaging over time. Importantly, these consistent findings were independent of tumor type, immunocompetence, and route of MSC delivery.
Stem Cells 08/2009; 27(10):2614-23. · 7.78 Impact Factor
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[show abstract]
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ABSTRACT: Multipotent mesenchymal stromal/stem cells (MSC) have shown potential clinical utility. However, previous assessments of MSC behavior in recipients have relied on visual detection in host tissue following sacrifice, failing to monitor in vivo MSC dispersion in a single animal and limiting the number of variables that can be observed concurrently. In this study, we used noninvasive, in vivo bioluminescent imaging to determine conditions under which MSC selectively engraft in sites of inflammation. MSC modified to express firefly luciferase (ffLuc-MSC) were injected into healthy mice or mice bearing inflammatory insults, and MSC localization was followed with bioluminescent imaging. The inflammatory insults investigated included cutaneous needle-stick and surgical incision wounds, as well as xenogeneic and syngeneic tumors. We also compared tumor models in which MSC were i.v. or i.p. delivered. Our results demonstrate that ffLuc-expressing human MSC (hMSC) systemically delivered to nontumor-bearing animals initially reside in the lungs, then egress to the liver and spleen, and decrease in signal over time. However, hMSC in wounded mice engraft and remain detectable only at injured sites. Similarly, in syngeneic and xenogeneic breast carcinoma-bearing mice, bioluminescent detection of systemically delivered MSC revealed persistent, specific colocalization with sites of tumor development. This pattern of tropism was also observed in an ovarian tumor model in which MSC were i.p. injected. In this study, we identified conditions under which MSC tropism and selective engraftment in sites of inflammation can be monitored by bioluminescent imaging over time. Importantly, these consistent findings were independent of tumor type, immunocompetence, and route of MSC delivery. STEM CELLS 2009;27:2614–2623
Stem Cells 07/2009; 27(10):2614 - 2623. · 7.78 Impact Factor
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ABSTRACT: Tumor associated fibroblasts (TAF), are essential for tumor progression providing both a functional and structural supportive environment. TAF, known as activated fibroblasts, have an established biological impact on tumorigenesis as matrix synthesizing or matrix degrading cells, contractile cells, and even blood vessel associated cells. The production of growth factors, cytokines, chemokines, matrix-degrading enzymes, and immunomodulatory mechanisms by these cells augment tumor progression by providing a suitable environment. There are several suggested origins of the TAF including tissue-resident, circulating, and epithelial-to-mesenchymal-transitioned cells.
We provide evidence that TAF are derived from mesenchymal stem cells (MSC) that acquire a TAF phenotype following exposure to or systemic recruitment into adenocarcinoma xenograft models including breast, pancreatic, and ovarian. We define the MSC derived TAF in a xenograft ovarian carcinoma model by the immunohistochemical presence of 1) fibroblast specific protein and fibroblast activated protein; 2) markers phenotypically associated with aggressiveness, including tenascin-c, thrombospondin-1, and stromelysin-1; 3) production of pro-tumorigenic growth factors including hepatocyte growth factor, epidermal growth factor, and interleukin-6; and 4) factors indicative of vascularization, including alpha-smooth muscle actin, desmin, and vascular endothelial growth factor. We demonstrate that under long-term tumor conditioning in vitro, MSC express TAF-like proteins. Additionally, human MSC but not murine MSC stimulated tumor growth primarily through the paracrine production of secreted IL6.
Our results suggest the dependence of in vitro Skov-3 tumor cell proliferation is due to the presence of tumor-stimulated MSC secreted IL6. The subsequent TAF phenotype arises from the MSC which ultimately promotes tumor growth through the contribution of microvascularization, stromal networks, and the production of tumor-stimulating paracrine factors.
PLoS ONE 02/2009; 4(4):e4992. · 4.09 Impact Factor
