In-vivo monitoring and quantification of breast cancer growth dynamics with non-invasive intravital mesoscopic fluorescence molecular tomography

Preclinical breast tumor models are an invaluable tool to systematically study tumor progression and treatment response, yet methods to non-invasively monitor the involved molecular and mechanistic properties under physiologically relevant conditions are limited. Here we present an intravital mesoscopic fluorescence molecular tomography (henceforth IFT) approach that is capable of tracking fluorescently labeled tumor cells in a quantitative manner inside the mammary gland of living mice. Our mesoscopic approach is entirely non-invasive and thus permits prolonged observational periods of several months. The relatively high sensitivity and spatial resolution further enable inferring the overall number of oncogene-expressing tumor cells as well as their tumor volume over the entire cycle from early tumor growth to residual disease following the treatment phase. We find that sheer tumor volume, as commonly assessed by other imaging modalities, is not well correlated to tumor cell quantity, hence our IFT approach is a promising new method for studying tumor growth dynamics in a quantitative and longitudinal fashion in-vivo.

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Intravital mesoscopic fluorescence molecular tomography allows non-invasive in vivo monitoring and quantification of breast cancer growth dynamics

Communications Biology ◽

10.1038/s42003-021-02063-8 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Mehmet S. Ozturk ◽

Marta G. Montero ◽

Ling Wang ◽

Lucas M. Chaible ◽

Martin Jechlinger ◽

...

Keyword(s):

Tumor Growth ◽

Tumor Cells ◽

Residual Disease ◽

Growth Dynamics ◽

Treatment Phase ◽

High Sensitivity ◽

Fluorescence Molecular Tomography ◽

Non Invasive ◽

Early Tumor

AbstractPreclinical breast tumor models are an invaluable tool to systematically study tumor progression and treatment response, yet methods to non-invasively monitor the involved molecular and mechanistic properties under physiologically relevant conditions are limited. Here we present an intravital mesoscopic fluorescence molecular tomography (henceforth IFT) approach that is capable of tracking fluorescently labeled tumor cells in a quantitative manner inside the mammary gland of living mice. Our mesoscopic approach is entirely non-invasive and thus permits prolonged observational periods of several months. The relatively high sensitivity and spatial resolution further enable inferring the overall number of oncogene-expressing tumor cells as well as their tumor volume over the entire cycle from early tumor growth to residual disease following the treatment phase. Our IFT approach is a promising method for studying tumor growth dynamics in a quantitative and longitudinal fashion in-vivo.

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Antagonist Anti-CD40 Antibody CHIR-12.12 Causes Tumor Regression and Prolongs Survival in Multiple Myeloma Xenograft Models.

Blood ◽

10.1182/blood.v104.11.4888.4888 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4888-4888

Author(s):

Li Long ◽

Xia Tong ◽

Montesa Patawaran ◽

Lea Aukerman ◽

Bahija Jallal ◽

...

Keyword(s):

Multiple Myeloma ◽

Tumor Growth ◽

Tumor Cells ◽

Tumor Volume ◽

Dependent Manner ◽

Human Multiple Myeloma ◽

Xenograft Models ◽

Dose Dependent

Abstract CD40 is expressed on most B cell malignancies including multiple myeloma and represents an attractive target for antibody therapy. We have generated a novel, highly potent, fully human antagonistic anti-CD40 monoclonal antibody, CHIR-12.12, using XenoMouse® mice (Abgenix, Inc). The antibody can mediate anti-tumor activity potentially by at least two mechanisms: CHIR-12.12 can block CD40-ligand mediated survival signals and it can lyse tumor cells by antibody-dependent cellular cytotoxicity (ADCC). We have previously reported that CHIR-12.12 mediates stronger killing of CD40- and CD20-expressing lymphoma cells than rituximab by ADCC in vitro and significantly inhibits the growth of both rituximab-responsive and rituximab-resistant human lymphoma xenografts in vivo. In this study, we examined in vitro and in vivo efficacy of CHIR-12.12 against human multiple myeloma. The human MM cell line IM-9, which expresses both CD40 and CD20, the target antigen for CHIR-12.12 and rituximab respectively was used for the study. CHIR-12.12 induced lysis of target tumor cells by ADCC in a dose dependent manner reaching maximum cell lysis at 0.1ug/ml concentration. The maximum specific lysis of IM-9 cells by CHIR-12.12 was greater than the lysis induced by rituximab (64% vs 45 %, n=3, p<0.01). In addition, the EC50 of CHIR-12.12 was on average 5.9 picomolar, which was 10-fold lower than the EC50 of rituximab. Greater ADCC by CHIR-12.12 was not due to higher density of CD40 molecules on the target tumor cells compared to CD20 molecules. IM-9 cells expressed 35590 ±8858 CD40 molecules compared to 93783 ± 2247 CD20 molecules. The in vivo CHIR-12.12 efficacy was then evaluated in IM-9 xenograft model. In an un-staged conditional survival model, where treatment began one day after intravenous inoculation of IM-9 tumor cells, CHIR-12.12 significantly prolonged the survival of tumor-bearing mice in a dose-dependent manner with 60% survival in the 0.1 mg/kg CHIR-12.12 treated group and 80% survival in the 1 and 10 mg/kg groups respectively on day 56 (Log Rank Test: P<0.01 and P<0.001, respectively). All animals in the control IgG1 and bortezomib treated groups were terminated between day 18 and day 26 due to severe disease related to tumor development (i.e., hind limb paralysis and significant body weight loss). In a staged subcutaneous model, where treatment began once the tumor volume was 150–200mm3, CHIR-12.12 administered weekly at 0.1, 1 and 10 mg/kg significantly inhibited tumor growth with a tumor volume reduction of 17% (P>0.05), 34% (P<0.01) and 44% (P<0.001) respectively. Bortezomib, when tested at 0.5 mg/kg twice a week did not inhibit tumor growth. At the maximally tolerated dose (MTD) of 1 mg/kg twice a week, bortezomib inhibited tumor growth by 30% (P<0.01). Taken together, these data demonstrate that the anti-CD40 mAb CHIR-12.12 has potent activity against human multiple myeloma in vitro and xenograft models in vivo.

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Melatonin modifies tumor hypoxia and metabolism by inhibiting HIF-1α and energy metabolic pathway in the in vitro and in vivo models of breast cancer

Melatonin Research ◽

10.32794/mr11250042 ◽

2019 ◽

Vol 2 (4) ◽

pp. 83-98 ◽

Cited By ~ 2

Author(s):

André De Lima Mota ◽

Bruna Vitorasso Jardim-Perassi ◽

Tialfi Bergamin De Castro ◽

Jucimara Colombo ◽

Nathália Martins Sonehara ◽

...

Keyword(s):

Breast Cancer ◽

Glucose Metabolism ◽

Tumor Growth ◽

Tumor Cells ◽

Carbonic Anhydrases ◽

In Vivo Models ◽

Ca Ix ◽

Gene And Protein Expression

Breast cancer is the most common cancer among women and has a high mortality rate. Adverse conditions in the tumor microenvironment, such as hypoxia and acidosis, may exert selective pressure on the tumor, selecting subpopulations of tumor cells with advantages for survival in this environment. In this context, therapeutic agents that can modify these conditions, and consequently the intratumoral heterogeneity need to be explored. Melatonin, in addition to its physiological effects, exhibits important anti-tumor actions which may associate with modification of hypoxia and Warburg effect. In this study, we have evaluated the action of melatonin on tumor growth and tumor metabolism by different markers of hypoxia and glucose metabolism (HIF-1α, glucose transporters GLUT1 and GLUT3 and carbonic anhydrases CA-IX and CA-XII) in triple negative breast cancer model. In an in vitro study, gene and protein expressions of these markers were evaluated by quantitative real-time PCR and immunocytochemistry, respectively. The effects of melatonin were also tested in a MDA-MB-231 xenograft animal model. Results showed that melatonin treatment reduced the viability of MDA-MB-231 cells and tumor growth in Balb/c nude mice (p <0.05). The treatment significantly decreased HIF-1α gene and protein expression concomitantly with the expression of GLUT1, GLUT3, CA-IX and CA-XII (p <0.05). These results strongly suggest that melatonin down-regulates HIF-1α expression and regulates glucose metabolism in breast tumor cells, therefore, controlling hypoxia and tumor progression.

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ANTITUMOR EFFECT OF COLLOIDAL SILVER BISILICATE IN EXPERIMENTAL IN VITRO AND IN VIVO STUDIES

Problems in oncology ◽

10.37469/0507-3758-2019-65-5-760-765 ◽

2019 ◽

Vol 65 (5) ◽

pp. 760-765

Author(s):

Margarita Tyndyk ◽

Irina Popovich ◽

A. Malek ◽

R. Samsonov ◽

N. Germanov ◽

...

Keyword(s):

Antitumor Activity ◽

Tumor Growth ◽

Tumor Cells ◽

Human Tumor ◽

Significant Inhibition ◽

In Vivo Studies ◽

Ehrlich Carcinoma ◽

In Vivo Experiments

The paper presents the results of the research on the antitumor activity of a new drug - atomic clusters of silver (ACS), the colloidal solution of nanostructured silver bisilicate Ag6Si2O7 with particles size of 1-2 nm in deionized water. In vitro studies to evaluate the effect of various ACS concentrations in human tumor cells cultures (breast cancer, colon carcinoma and prostate cancer) were conducted. The highest antitumor activity of ACS was observed in dilutions from 2.7 mg/l to 5.1 mg/l, resulting in the death of tumor cells in all studied cell cultures. In vivo experiments on transplanted Ehrlich carcinoma model in mice consuming 0.75 mg/kg ACS with drinking water revealed significant inhibition of tumor growth since the 14th day of experiment (maximally by 52% on the 28th day, p < 0.05) in comparison with control. Subcutaneous injections of 2.5 mg/kg ACS inhibited Ehrlich's tumor growth on the 7th and 10th days of the experiment (p < 0.05) as compared to control.

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Promising potential of [177Lu]Lu-DOTA-folate to enhance tumor response to immunotherapy—a preclinical study using a syngeneic breast cancer model

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-020-05054-9 ◽

2020 ◽

Author(s):

Patrycja Guzik ◽

Klaudia Siwowska ◽

Hsin-Yu Fang ◽

Susan Cohrs ◽

Peter Bernhardt ◽

...

Keyword(s):

Tumor Growth ◽

Survival Time ◽

Tumor Cells ◽

Median Survival ◽

Breast Tumor ◽

Median Survival Time ◽

Therapy Outcome ◽

Minor Effect

Abstract Purpose It was previously demonstrated that radiation effects can enhance the therapy outcome of immune checkpoint inhibitors. In this study, a syngeneic breast tumor mouse model was used to investigate the effect of [177Lu]Lu-DOTA-folate as an immune stimulus to enhance anti-CTLA-4 immunotherapy. Methods In vitro and in vivo studies were performed to characterize NF9006 breast tumor cells with regard to folate receptor (FR) expression and the possibility of tumor targeting using [177Lu]Lu-DOTA-folate. A preclinical therapy study was performed over 70 days with NF9006 tumor-bearing mice that received vehicle only (group A); [177Lu]Lu-DOTA-folate (5 MBq; 3.5 Gy absorbed tumor dose; group B); anti-CTLA-4 antibody (3 × 200 μg; group C), or both agents (group D). The mice were monitored regarding tumor growth over time and signs indicating adverse events of the treatment. Results [177Lu]Lu-DOTA-folate bound specifically to NF9006 tumor cells and tissue in vitro and accumulated in NF9006 tumors in vivo. The treatment with [177Lu]Lu-DOTA-folate or an anti-CTLA-4 antibody had only a minor effect on NF9006 tumor growth and did not substantially increase the median survival time of mice (23 day and 19 days, respectively) as compared with untreated controls (12 days). [177Lu]Lu-DOTA-folate sensitized, however, the tumors to anti-CTLA-4 immunotherapy, which became obvious by reduced tumor growth and, hence, a significantly improved median survival time of mice (> 70 days). No obvious signs of adverse effects were observed in treated mice as compared with untreated controls. Conclusion Application of [177Lu]Lu-DOTA-folate had a positive effect on the therapy outcome of anti-CTLA-4 immunotherapy. The results of this study may open new perspectives for future clinical translation of folate radioconjugates.

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Irradiation-Modulated Murine Brain Microenvironment Enhances GL261-Tumor Growth and Inhibits Anti-PD-L1 Immunotherapy

Frontiers in Oncology ◽

10.3389/fonc.2021.693146 ◽

2021 ◽

Vol 11 ◽

Author(s):

Joel R. Garbow ◽

Tanner M. Johanns ◽

Xia Ge ◽

John A. Engelbach ◽

Liya Yuan ◽

...

Keyword(s):

Tumor Growth ◽

Tumor Cells ◽

Primary Brain Tumor ◽

Brain Parenchyma ◽

Response To Treatment ◽

Separate Experiment ◽

Lesion Volume ◽

Activated Microglia ◽

Significant Difference

PurposeClinical evidence suggests radiation induces changes in the brain microenvironment that affect subsequent response to treatment. This study investigates the effect of previous radiation, delivered six weeks prior to orthotopic tumor implantation, on subsequent tumor growth and therapeutic response to anti-PD-L1 therapy in an intracranial mouse model, termed the Radiation Induced Immunosuppressive Microenvironment (RI2M) model.Method and MaterialsC57Bl/6 mice received focal (hemispheric) single-fraction, 30-Gy radiation using the Leksell GammaKnife® Perfexion™, a dose that does not produce frank/gross radiation necrosis. Non-irradiated GL261 glioblastoma tumor cells were implanted six weeks later into the irradiated hemisphere. Lesion volume was measured longitudinally by in vivo MRI. In a separate experiment, tumors were implanted into either previously irradiated (30 Gy) or non-irradiated mouse brain, mice were treated with anti-PD-L1 antibody, and Kaplan-Meier survival curves were constructed. Mouse brains were assessed by conventional hematoxylin and eosin (H&E) staining, IBA-1 staining, which detects activated microglia and macrophages, and fluorescence-activated cell sorting (FACS) analysis.ResultsTumors in previously irradiated brain display aggressive, invasive growth, characterized by viable tumor and large regions of hemorrhage and necrosis. Mice challenged intracranially with GL261 six weeks after prior intracranial irradiation are unresponsive to anti-PD-L1 therapy. K-M curves demonstrate a statistically significant difference in survival for tumor-bearing mice treated with anti-PD-L1 antibody between RI2M vs. non-irradiated mice. The most prominent immunologic change in the post-irradiated brain parenchyma is an increased frequency of activated microglia.ConclusionsThe RI2M model focuses on the persisting (weeks-to-months) impact of radiation applied to normal, control-state brain on the growth characteristics and immunotherapy response of subsequently implanted tumor. GL261 tumors growing in the RI2M grew markedly more aggressively, with tumor cells admixed with regions of hemorrhage and necrosis, and showed a dramatic loss of response to anti-PD-L1 therapy compared to tumors in non-irradiated brain. IHC and FACS analyses demonstrate increased frequency of activated microglia, which correlates with loss of sensitivity to checkpoint immunotherapy. Given that standard-of-care for primary brain tumor following resection includes concurrent radiation and chemotherapy, these striking observations strongly motivate detailed assessment of the late effects of the RI2M on tumor growth and therapeutic efficacy.

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Highly Differentiated Anti-CD47 Antibody, AO-176, Potently Inhibits Hematologic Malignancies Alone and in Combination

Blood ◽

10.1182/blood-2019-126298 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1844-1844

Author(s):

John Richards ◽

Myriam N Bouchlaka ◽

Robyn J Puro ◽

Ben J Capoccia ◽

Ronald R Hiebsch ◽

...

Keyword(s):

Multiple Myeloma ◽

Combination Therapy ◽

Tumor Growth ◽

Growth Inhibition ◽

Tumor Cells ◽

Tumor Growth Inhibition ◽

Employment Equity ◽

Equity Ownership

AO-176 is a highly differentiated, humanized anti-CD47 IgG2 antibody that is unique among agents in this class of checkpoint inhibitors. AO-176 works by blocking the "don't eat me" signal, the standard mechanism of anti-CD47 antibodies, but also by directly killing tumor cells. Importantly, AO-176 binds preferentially to tumor cells, compared to normal cells, and binds even more potently to tumors in their acidic microenvironment (low pH). Hematological neoplasms are the fourth most frequently diagnosed cancers in both men and women and account for approximately 10% of all cancers. Here we describe AO-176, a highly differentiated anti-CD47 antibody that potently targets hematologic cancers in vitro and in vivo. As a single agent, AO-176 not only promotes phagocytosis (15-45%, EC50 = 0.33-4.1 µg/ml) of hematologic tumor cell lines (acute myeloid leukemia, non-Hodgkin's lymphoma, multiple myeloma, and T cell leukemia) but also directly targets and kills tumor cells (18-46% Annexin V positivity, EC50 = 0.63-10 µg/ml) in a non-ADCC manner. In combination with agents targeting CD20 (rituximab) or CD38 (daratumumab), AO-176 mediates enhanced phagocytosis of lymphoma and multiple myeloma cell lines, respectively. In vivo, AO-176 mediates potent monotherapy tumor growth inhibition of hematologic tumors including Raji B cell lymphoma and RPMI-8226 multiple myeloma xenograft models in a dose-dependent manner. Concomitant with tumor growth inhibition, immune cell infiltrates were observed with elevated numbers of macrophage and dendritic cells, along with increased pro-inflammatory cytokine levels in AO-176 treated animals. When combined with bortezomib, AO-176 was able to elicit complete tumor regression (100% CR in 10/10 animals treated with either 10 or 25 mg/kg AO-176 + 1 mg/kg bortezomib) with no detectable tumor out to 100 days at study termination. Overall survival was also greatly improved following combination therapy compared to animals treated with bortezomib or AO-176 alone. These data show that AO-176 exhibits promising monotherapy and combination therapy activity, both in vitro and in vivo, against hematologic cancers. These findings also add to the previously reported anti-tumor efficacy exhibited by AO-176 in solid tumor xenografts representing ovarian, gastric and breast cancer. With AO-176's highly differentiated MOA and binding characteristics, it may have the potential to improve upon the safety and efficacy profiles relative to other agents in this class. AO-176 is currently being evaluated in a Phase 1 clinical trial (NCT03834948) for the treatment of patients with select solid tumors. Disclosures Richards: Arch Oncology Inc.: Employment, Equity Ownership, Other: Salary. Bouchlaka:Arch Oncology Inc.: Consultancy, Equity Ownership. Puro:Arch Oncology Inc.: Employment, Equity Ownership. Capoccia:Arch Oncology Inc.: Employment, Equity Ownership. Hiebsch:Arch Oncology Inc.: Employment, Equity Ownership. Donio:Arch Oncology Inc.: Employment, Equity Ownership. Wilson:Arch Oncology Inc.: Employment, Equity Ownership. Chakraborty:Arch Oncology Inc.: Employment, Equity Ownership. Sung:Arch Oncology Inc.: Employment, Equity Ownership. Pereira:Arch Oncology Inc.: Employment, Equity Ownership.

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DRES-07. TMZ-LEV- IFN COCKTAIL REGIMEN SIGNIFICANTLY INHIBITED THE GROWTH OF GLIOMA IN VIVO

Neuro-Oncology ◽

10.1093/neuonc/noz175.295 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi72-vi73

Author(s):

Xiang-rong Ni ◽

Jing Wang ◽

Fu-rong Chen ◽

Hai-ping Cai ◽

Yan-jiao Yu ◽

...

Keyword(s):

Protein Expression ◽

Tumor Growth ◽

Tumor Volume ◽

Control Group ◽

First Line ◽

Killing Effect ◽

Treatment Groups ◽

Mgmt Protein ◽

Tumor Killing

Abstract OBJECTIVE Temozolomide (TMZ), is the first line chemotherapeutic drug for glioma. Previous studies have suggested that interferon (IFN) and levetiracetam (LEV) could respectively reverse the resistance of TMZ by down-regulating MGMT expression. This study, we aim to investigate the therapeutic effect of a cocktail chemotherapy regimen combining TMZ, LEV, IFN in vivo. METHODS Glioma cell lines U251 and SKMG-4 (MGMT protein expression positive), U138 and GSC-1(MGMT protein expression negative) were used for producing xenograft tumors. The xenograft tumors were established by subcutaneously injecting 1×106 glioma cells into female BALB/C nude mice and divided into 5 treatment groups: Control, TMZ, TMZ+IFN, TMZ+LEV, TMZ+LEV+IFN. The treatment with TMZ (50 mg/kg, i.p.), IFN (2×105 IU, s.c.), LEV (150 mg/kg, i.p.) once a day for five consecutive days and xenograft tumors were measured every two days. RESULTS We identified that U138, U251, SKMG-4 tumor growth among TMZ, TMZ+IFN, TMZ+LEV, TMZ+LEV+IFN were all significantly inhibited (P< 0.05), compared with the control. As for U251 and SKMG-4, tumor killing effect of all 4 treatment groups were not different (P > 0.05). In the treatment of mice bearing U138 glioma, the tumor weight of TMZ+LEV+IFN (0.2688±0.1169 g) group was the lowest and significantly lower than that of TMZ+LEV (0.6574±0.08174g, P=0.0261), TMZ+IFN(0.6108±0.07317 g, P=0.0381), and TMZ (0.9054±0.07154 g, P=0.0017) group. Glioma stem cells GSC-1 was highly resistant to TMZ, tumor volume of TMZ group was not different from control group (P >0.05). While compared with TMZ (1.993±0.1274 g) group, in TMZ+IFN (1.506±0.1223g, P=0.0203), TMZ+LEV (1.178±0.1807g, P=0.0042), and TMZ+LEV+IFN (1.049±0.2171 g, P=0.0038) groups, GSC-1 tumor growth were significantly inhibited(P< 0.05). CONCLUSION Our data demonstrate that both IFN and LEV can sensitize TMZ effect on glioma in vivo, even for MGMT(+) tumors, and TMZ-LEV-IFN cocktail regimen seems the best. Key words: glioma, TMZ, LEV, IFN

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Tumor quiescence: elevating SOX2 in diverse tumor cell types downregulates a broad spectrum of the cell cycle machinery and inhibits tumor growth

BMC Cancer ◽

10.1186/s12885-020-07370-7 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Ethan P. Metz ◽

Erin L. Wuebben ◽

Phillip J. Wilder ◽

Jesse L. Cox ◽

Kaustubh Datta ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Tumor Growth ◽

Tumor Cell ◽

Tumor Cells ◽

Molecular Mechanisms ◽

Cell Types ◽

Cell Cycle Machinery

Abstract Background Quiescent tumor cells pose a major clinical challenge due to their ability to resist conventional chemotherapies and to drive tumor recurrence. Understanding the molecular mechanisms that promote quiescence of tumor cells could help identify therapies to eliminate these cells. Significantly, recent studies have determined that the function of SOX2 in cancer cells is highly dose dependent. Specifically, SOX2 levels in tumor cells are optimized to promote tumor growth: knocking down or elevating SOX2 inhibits proliferation. Furthermore, recent studies have shown that quiescent tumor cells express higher levels of SOX2 compared to adjacent proliferating cells. Currently, the mechanisms through which elevated levels of SOX2 restrict tumor cell proliferation have not been characterized. Methods To understand how elevated levels of SOX2 restrict the proliferation of tumor cells, we engineered diverse types of tumor cells for inducible overexpression of SOX2. Using these cells, we examined the effects of elevating SOX2 on their proliferation, both in vitro and in vivo. In addition, we examined how elevating SOX2 influences their expression of cyclins, cyclin-dependent kinases (CDKs), and p27Kip1. Results Elevating SOX2 in diverse tumor cell types led to growth inhibition in vitro. Significantly, elevating SOX2 in vivo in pancreatic ductal adenocarcinoma, medulloblastoma, and prostate cancer cells induced a reversible state of tumor growth arrest. In all three tumor types, elevation of SOX2 in vivo quickly halted tumor growth. Remarkably, tumor growth resumed rapidly when SOX2 returned to endogenous levels. We also determined that elevation of SOX2 in six tumor cell lines decreased the levels of cyclins and CDKs that control each phase of the cell cycle, while upregulating p27Kip1. Conclusions Our findings indicate that elevating SOX2 above endogenous levels in a diverse set of tumor cell types leads to growth inhibition both in vitro and in vivo. Moreover, our findings indicate that SOX2 can function as a master regulator by controlling the expression of a broad spectrum of cell cycle machinery. Importantly, our SOX2-inducible tumor studies provide a novel model system for investigating the molecular mechanisms by which elevated levels of SOX2 restrict cell proliferation and tumor growth.

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Regulation of Parathyroid Hormone-Related Peptide by Estradiol: Effect on Tumor Growth and Metastasis in Vitro and in Vivo

Endocrinology ◽

10.1210/en.2005-0062 ◽

2005 ◽

Vol 146 (7) ◽

pp. 2885-2894 ◽

Cited By ~ 22

Author(s):

S. A. Rabbani ◽

P. Khalili ◽

A. Arakelian ◽

H. Pizzi ◽

G. Chen ◽

...

Keyword(s):

Breast Cancer ◽

Cell Growth ◽

Tumor Growth ◽

Tumor Volume ◽

In Vivo Studies ◽

Promoting Effect ◽

X Ray ◽

Tumor Bearing ◽

Tumor Growth And Metastasis

Abstract We evaluated the capacity of estradiol (E2) to regulate PTHrP production, cell growth, tumor growth, and metastasis to the skeleton in breast cancer. In estrogen receptor (ER)-negative human breast cancer cells, MDA-MB-231, and cells transfected with full-length cDNA encoding ER (S-30), E2 caused a marked decrease in cell growth and PTHrP production, effects that were abrogated by anti-E2 tamoxifen. E2 also inhibited PTHrP promoter activity in S-30 cells. For in vivo studies, MDA-MB-231 and S-30 cells were inoculated into the mammary fat pad of female BALB/c nu.nu mice. Animals receiving S-30 cells developed tumors of significantly smaller volume compared with MDA-MB-231 tumor-bearing animals. This change in tumor volume was reversed when S-30 cells were inoculated into ovariectomized (OVX) hosts. Inoculation of MDA-MB-231 cells into the left ventricle resulted in the development of lesions in femora and tibia as determined by x-ray analysis. In contrast, these lesions were significantly smaller in volume and number in animals inoculated with S-30, and this lower incidence was reversed in OVX animals. Bone histological analysis showed that the tumor volume to tissue volume ratio was comparable with that seen by x-ray. Immunohistochemical analysis showed that PTHrP production was inhibited in S-30 group and restored to levels comparable to that seen in MDA-MB-231 tumor-bearing animals when S-30 cells were inoculated in OVX animals. Collectively these studies show that E2 production is inversely correlated with PTHrP production and that the growth-promoting effect of PTHrP has a direct impact on tumor growth at both nonskeletal and skeletal sites.

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