Breast cancer cells frequently home to the bone marrow, where they may enter a dormant state before forming a bone metastasis. Several members of the interleukin-6 (IL-6) cytokine family are implicated in breast cancer bone colonization, but the role for the IL-6 cytokine leukemia inhibitory factor (LIF) in this process is unknown. We tested the hypothesis that LIF provides a pro-dormancy signal to breast cancer cells in the bone. In breast cancer patients, LIF receptor (LIFR) levels are lower with bone metastases and are significantly and inversely correlated with patient outcome and hypoxia gene activity. Hypoxia also reduces the LIFR:STAT3:SOCS3 signaling pathway in breast cancer cells. Loss of the LIFR or STAT3 enables otherwise dormant breast cancer cells to down-regulate dormancy, quiescence, and cancer stem cell-associated genes, and to proliferate in and specifically colonize the bone, suggesting LIFR:STAT3 signaling confers a dormancy phenotype in breast cancer cells disseminated to bone.

Cultivated murine bone marrow mesenchymal stem cells (MSCs) frequently accumulate chromosome abnormalities, become oncogenically transformed, and generate sarcomas when transplanted in mice. Although human MSCs appear to be more resistant, oncogenic transformation has also been observed in MSCs cultivated past the senescence phase. Cell therapy for tissue regeneration using human autologous MSCs requires transplantation of cells previously expanded in vitro. Thus, an important concern is to determine if oncogenic transformation is a necessary outcome of the expansion procedures. We have analyzed the proliferation capacity, organ colonization, and oncogenicity of enhanced green fluorescent protein and luciferase-labeled human adipose tissue-derived mesenchymal stem cells (hAMSCs), implanted in immunocompromised mice during a prolonged time period (8 months) using a non-invasive bioluminescence imaging procedure. Our data indicates that the liver was the preferred target organ for colonization by intramuscular or intravenous implantation of hAMSCs. The implanted cells tended to maintain a steady state, population did not proliferate rapidly after implantation, and no detectable chromosomal abnormalities nor tumors formed during the 8 months of residence in the host's tissues. It would appear that hAMSCs, contrary to their murine correlatives, could be safe candidates for autologous cell therapy procedures since in our experiments they show undetectable predisposition to oncogenic transformation after cultivation in vitro and implantation in mice.

It is well known that tumor cells migrate from the primary lesion to distant sites to form metastases and that these lesions limit patient outcome in a majority of cases. However the extent to which radiation influences this process and to which migration in turn alters radiation response remains controversial. There are preclinical and clinical reports showing that focal radiotherapy can both increase the development of distant metastasis, as well as that it can induce the regression of established metastases through the abscopal effect. More recently, preclinical studies have suggested that radiation can attract migrating tumor cells and may thereby facilitate tumor recurrence. In this review, we summarize these phenomena and their potential mechanisms of action, and evaluate their significance for modern radiation therapy strategies.

Purpose: To efficiently translate experimental methods from bench to bedside, it is imperative that laboratory models of cancer mimic human disease as closely as possible. In this study, we sought to compare patterns of hypoxia in several standard and emerging mouse models of lung cancer to establish the appropriateness of each for evaluating the role of oxygen in lung cancer progression and therapeutic response.Experimental Design: Subcutaneous and orthotopic human A549 lung carcinomas growing in nude mice as well as spontaneous K-ras or Myc-induced lung tumors grown in situ or subcutaneously were studied using fluorodeoxyglucose and fluoroazomycin arabinoside positron emission tomography, and postmortem by immunohistochemical observation of the hypoxia marker pimonidazole. The response of these models to the hypoxia-activated cytotoxin PR-104 was also quantified by the formation of γH2AX foci in vitro and in vivo. Finally, our findings were compared with oxygen electrode measurements of human lung cancers.Results: Minimal fluoroazomycin arabinoside and pimonidazole accumulation was seen in tumors growing within the lungs, whereas subcutaneous tumors showed substantial trapping of both hypoxia probes. These observations correlated with the response of these tumors to PR-104, and with the reduced incidence of hypoxia in human lung cancers relative to other solid tumor types.Conclusions: These findings suggest that in situ models of lung cancer in mice may be more reflective of the human disease, and encourage judicious selection of preclinical tumor models for the study of hypoxia imaging and antihypoxic cell therapies.

Summary We present evidence that irradiation of breast tumors can attract migrating breast cancer cells. Granulocyte-macrophage colony stimulating factor (GM-CSF) produced by tumor cells in response to radiation stimulates the recruitment of migrating tumor cells to irradiated tumors, suggesting a mechanism of tumor recurrence after radiation facilitated by transit of unirradiated, viable circulating tumor cells to irradiated tumors. Data supporting this hypothesis is presented through in vitro invasion assays and in vivo orthotopic models of breast cancer.

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Although radiotherapy (RT) decreases the incidence of locoregional recurrence in breast cancer, patients with triple-negative breast cancer (TNBC) have increased risk of local recurrence following breast-conserving therapy. The relationship between RT and local recurrence is unknown. Here, we tested the hypothesis that recurrence in some instances is due to the attraction of circulating tumor cells to irradiated tissues. To evaluate the effect of absolute lymphocyte count on local recurrence after RT in patients with TNBC, we analyzed radiation effects on tumor and immune cell recruitment to tissues in an orthotopic breast cancer model. Recurrent patients exhibited a prolonged low absolute lymphocyte count when compared with nonrecurrent patients following RT. Recruitment of tumor cells to irradiated normal tissues was enhanced in the absence of CD8 T cells. Macrophages (CD11bF480) preceded tumor cell infiltration and were recruited to tissues following RT. Tumor cell recruitment was mitigated by inhibiting macrophage infiltration using maraviroc, an FDA-approved CCR5 receptor antagonist. Our work poses the intriguing possibility that excessive macrophage infiltration in the absence of lymphocytes promotes local recurrence after RT. This combination thus defines a high-risk group of patients with TNBC. This study establishes the importance of macrophages in driving tumor cell recruitment to sites of local radiation therapy and suggests that this mechanism contributes to local recurrence in women with TNBC that are also immunosuppressed. http://cancerres.aacrjournals.org/content/canres/78/15/4241/F1.large.jpg .

Human adipose tissue mesenchymal stromal cells (AMSCs) share common traits, including similar differentiation potential and cell surface markers, with their bone marrow counterparts. Owing to their general availability, higher abundance and ease of isolation AMSCs may be convenient autologous delivery vehicles for localized tumor therapy. We demonstrate a model for tumor therapy development based on the use of AMSCs expressing renilla luciferase and thymidine kinase, as cellular vehicles for ganciclovir-mediated bystander killing of firefly luciferase expressing tumors, and noninvasive bioluminescence imaging to continuously monitor both, tumor cells and AMSCs. We show that the therapy delivering AMSCs survive long time within tumors, optimize the ratio of AMSCs to tumor cells for therapy, and asses the therapeutic effect in real time. Treatment of mice bearing prostate tumors plus therapeutic AMSCs with the prodrug ganciclovir induced bystander killing effect, reducing the number of tumor cells to 1.5 % that of control tumors. Thus, AMSCs could be useful vehicles to deliver localized therapy, with potential for clinical application in inoperable tumors and surgical borders after tumor resection. This approach, useful to evaluate efficiency of therapeutic models, should facilitate the selection of cell types, dosages, therapeutic agents and treatment protocols for cell-based therapies of specific tumors.