Stem Cells Drive Tumor Growth Research Articles

A TOX-ic axis of epigenetic stem cell maintenance and chemoresistance in colon cancer.

Cancer stem cells drive tumor growth and survival via self-renewal and therapeutic resistance, but the upstream mechanisms are not well defined. In this issue of PLOS Biology, a study in colon cancer reveals a new signalling network that links epigenetic regulation to these phenotypes.

A mathematical model for IL-6-mediated, stem cell driven tumor growth and targeted treatment.

Targeting key regulators of the cancer stem cell phenotype to overcome their critical influence on tumor growth is a promising new strategy for cancer treatment. Here we present a modeling framework that operates at both the cellular and molecular levels, for investigating IL-6 mediated, cancer stem cell driven tumor growth and targeted treatment with anti-IL6 antibodies. Our immediate goal is to quantify the influence of IL-6 on cancer stem cell self-renewal and survival, and to characterize the subsequent impact on tumor growth dynamics. By including the molecular details of IL-6 binding, we are able to quantify the temporal changes in fractional occupancies of bound receptors and their influence on tumor volume. There is a strong correlation between the model output and experimental data for primary tumor xenografts. We also used the model to predict tumor response to administration of the humanized IL-6R monoclonal antibody, tocilizumab (TCZ), and we found that as little as 1mg/kg of TCZ administered weekly for 7 weeks is sufficient to result in tumor reduction and a sustained deceleration of tumor growth.

Agent-Based Modeling of Cancer Stem Cell Driven Solid Tumor Growth.

Computational modeling of tumor growth has become an invaluable tool to simulate complex cell-cell interactions and emerging population-level dynamics. Agent-based models are commonly used to describe the behavior and interaction of individual cells in different environments. Behavioral rules can be informed and calibrated by in vitro assays, and emerging population-level dynamics may be validated with both in vitro and in vivo experiments. Here, we describe the design and implementation of a lattice-based agent-based model of cancer stem cell driven tumor growth.

Cancer Stem Cell Plasticity as Tumor Growth Promoter and Catalyst of Population Collapse.

It is increasingly argued that cancer stem cells are not a cellular phenotype but rather a transient state that cells can acquire, either through intrinsic signaling cascades or in response to environmental cues. While cancer stem cell plasticity is generally associated with increased aggressiveness and treatment resistance, we set out to thoroughly investigate the impact of different rates of plasticity on early and late tumor growth dynamics and the response to therapy. We develop an agent-based model of cancer stem cell driven tumor growth, in which plasticity is defined as a spontaneous transition between stem and nonstem cancer cell states. Simulations of the model show that plasticity can substantially increase tumor growth rate and invasion. At high rates of plasticity, however, the cells get exhausted and the tumor will undergo spontaneous remission in the long term. In a series of in silico trials, we show that such remission can be facilitated through radiotherapy. The presented study suggests that stem cell plasticity has rather complex, nonintuitive implications on tumor growth and treatment response. Further theoretical, experimental, and integrated studies are needed to fully decipher cancer stem cell plasticity and how it can be harnessed for novel therapeutic approaches.

Abstract 2685: Regulation of melanoma metastasis by malignant melanoma-initiating cell marker ABCB5.

Abstract Cancer stem cells drive tumor growth, including metastatic disease progression. ATP-binding cassette member B5 (ABCB5) expression identifies malignant melanoma initiating cells (MMICs), which are distinguishable from cancer bulk populations by their self-renewal and differentiation capacities, and pro-oncogenic interactions with the microenvironment. ABCB5 confers drug resistance in multiple human malignancies through its actions as a drug efflux transporter. Here, we demonstrate that ABCB5 also regulates melanoma metastasis. ABCB5 monoclonal antibody (mAb) treatment significantly inhibited metastasis development in highly immune-compromised NOD-scid IL2Rγnull mice carrying fully established human melanoma xenografts, independent of previously reported antibody-dependent cell-mediated cytotoxicity (ADCC) effects. ABCB5 mAb treatment was well tolerated, as indicated by equal body weights of treated mice and untreated controls. Moreover, ABCB5 mAb also inhibited melanoma cell invasive capacity, suggesting that ABCB5 regulates intravasation and/or extravasation of metastatic tumor cells. Furthermore, the average size of metastatic nodules in ABCB5 mAb-treated mice was significantly smaller than those in isotype control mAb-treated or untreated mice, indicating that ABCB5 also regulates proliferation of disseminated tumor cells. Expression profile analysis revealed that multiple known metastasis-associated genes are regulated by ABCB5. Rescue of their expression could reverse the anti-metastatic effects induced by ABCB5 inhibition. Thus, ABCB5 is not only a marker for MMICs, but functionally drives metastatic melanoma progression. Citation Format: Jie Ma, Allireza Alloo, Brian J. Wilson, Markus H. Frank. Regulation of melanoma metastasis by malignant melanoma-initiating cell marker ABCB5. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2685. doi:10.1158/1538-7445.AM2013-2685 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

Abstract 2448: Inhibiting the DLL4/Notch pathway delays tumor recurrence and decreases tumorigenicity in pancreatic cancer

Abstract It is becoming increasingly evident that cancer stem cells drive tumor growth and progression and are preferentially resistant to chemotherapy. Previously, we demonstrated that interfering with the Delta-like 4 ligand (DLL4)/Notch signaling by anti-DLL4 antibodies decreased tumor growth in a pancreatic xenograft model, delayed tumor recurrence following chemotherapy, and reduced the pancreatic cancer stem cell (CSC) fraction. In this study, we evaluated the response of seven pancreatic xenograft tumors to anti-DLL4 antibodies as a single agent and when combined with gemcitabine. Utilizing an in vivo limiting dilution assay, we tested the ability of cells from previously treated xenografts to re-grow tumors after serial transplantation to quantify CSCs. We discovered that anti-DLL4 was efficacious as a single agent in all seven tumor models. In all seven models, when anti-DLL4 was combined with gemcitabine, the therapy provided significant efficacy over that of gemcitabine alone. This combination therapy resulted in tumor regression in three of these models. The antibody therapy reduced the CSC fraction, while gemcitabine treatment alone enriched for the CSC. The chemotherapy/antibody combination further reduced the CSC fraction compared to anti-DLL4 alone. To analyze the mechanism of action of inhibiting DLL4-Notch signaling in tumor cells and in the host vasculature, we tested a human specific DLL4 mAb and a murine specific DLL4 mAb as single agents. Anti-human DLL4 reduced the tumorigenicity of pancreatic tumor cells, while anti-murine DLL4 had no effect on tumor initiating cell frequency. In a tumor recurrence model, the human specific DLL4 mAb delayed tumor recurrence following the termination of gemcitabine while the murine specific DLL4 mAb decreased the growth rate of recurrent tumors. The combination of human and murine targeting DLL4 mAbs produced an additive effect in reducing tumor recurrence. These data support the rationale for targeting the DLL4/Notch pathway in pancreatic cancer and provide evidence of the therapeutic utility of targeting pathways, such as Notch, required for cancer stem cell self renewal. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2448. doi:10.1158/1538-7445.AM2011-2448

Abstract 973: Targeting cancer stem cells by a novel anti-frizzled antibody inhibits pancreatic tumor growth and induces differentiation

Abstract Clinical management of pancreatic cancer over the past years has not been improved and this disease remains the fourth most common cause of cancer-related death. It has been suggested that cancer stem cells drive tumor growth and progression and are resistant to many current therapies. The WNT/beta-catenin pathway, which signals through the Frizzled (FZD) receptor family and co-receptors, plays an important role in regulating cell fate, stem cell self-renewal and maintenance. We have recently demonstrated that inhibition of WNT/beta-catenin pathway by an anti-FZD antibody 18R5 decreased tumorigenicity and induced differentiation in solid tumors. The present study evaluated the anti-tumor effect of OMP-18R5 in a panel of pancreatic tumors. In vivo studies using primary pancreatic xenograft tumor models showed that OMP-18R5 was efficacious against both high and low grade pancreatic tumors. Histologic and gene expression analyses indicated that the 18R5-mediated anti-tumor effect was associated with inhibition of WNT target genes while inducing of mucin expression and tumor cell differentiation. Furthermore, inclusion of OMP-18R5 delayed pancreatic tumor recurrence following termination of gemcitabine. The delay in tumor recurrence by OMP-18R5 treatment was associated with a decrease in cancer stem cell frequency. The combination of OMP-18R5 and gemcitabine further decreased cancer stem cell frequency compared to the single agents. Our findings provide a rationale to target cancer stem cells through interference with WNT/beta-catenin pathway as a therapeutic approach in pancreatic cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 973. doi:10.1158/1538-7445.AM2011-973

Abstract 4295: The combination of a novel anti-delta-like 4 ligand (DLL4) antibody with irinotecan inhibits growth of Kras-mutated colorectal tumors

Abstract Kras mutations in colorectal cancer (CRC) are associated with clinical resistance to treatment with the epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies. It has been suggested that cancer stem cells drive tumor growth and progression and are preferentially resistant to many current therapies. Delta-like 4 ligand (DLL4) is an important component of the Notch signaling pathway which is known to mediate stem cell self-renewal and vascular development. We have recently demonstrated that inhibition of human DLL4 in the tumor reduced cancer stem cell frequency, whereas inhibition of mouse DLL4 resulted in hyperproliferation of the tumor vasculature (Cell Stem Cell, 5:168-177, 2009). The goal of the present study is to extend the utility of anti-DLL4 in treatment of mutant Kras CRC. Consistent with clinical findings, mutant Kras colorectal xenograft tumors were generally insensitive to EGFR-targeted monoclonal antibody cetuximab and addition of anti-DLL4 did not further enhance cetuximab-mediated anti-tumor effect. In contrast, anti-DLL4 plus irinotecan was equally efficacious against both wild type and mutant Kras colon tumors. Gene expression analysis showed that anti-DLL4 affected vascular-related genes in the stroma and Notch target genes in the tumor and stroma. Further analysis of mutant Kras tumors indicated that anti-DLL4/ irinotecan combination produced a 5-fold decrease in colon cancer stem cell frequency compared to control antibody treated group. In conclusion, our findings provide a rationale for targeting cancer stem cells and tumor vasculature through inhibition of the DLL4/Notch signaling for treatment of CRC patients with Kras mutation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4295.

Abstract 15: Targeting cancer stem cells and vasculature by a novel anti-delta-like 4 ligand (DLL4) antibody inhibits triple-negative breast cancer tumor growth and delays tumor recurrence

Abstract Triple negative breast cancer (TNBC, ER−, PR− Her2−) accounts for about 10% of all types of breast cancer and is known to particularly aggressive and refractory to current therapies. Chemotherapeutic agents, such as taxanes, are currently the only treatment option for this type of breast cancer, however, these treatments often result in high rates of local and systemic relapse. It has been suggested that cancer stem cells drive tumor growth and progression and are preferentially resistant to many current therapies. Delta-like 4 ligand (DLL4) is an important component of the Notch signaling pathway which is known to mediate stem cell self-renewal and vascular development. We hypothesized that targeting cancer stem cells and the tumor vasculature by interfering with the DLL4/Notch pathway will improve treatment outcome. We developed anti-DLL4 antibodies that recognize either the human or murine protein and have potent binding and antagonist activities. We used these antibodies to investigate the role of DLL4 in triple negative breast cancer and to probe the mechanism in tumor and stromal cells in xenograft models derived from primary breast tumors. These studies showed that anti-DLL4 was efficacious as a single agent and in combination with paclitaxel (Taxol) against TNBC xenograft tumors. Gene expression analysis showed that anti-DLL4 affected vascular-related genes in the stroma and Notch target genes in the tumor and stroma. Inclusion of anti-DLL4 delayed breast tumor recurrence and decreased the growth rate of recurrent tumors following termination of paclitaxel treatment. Flow cytometric analysis showed that ESA+/CD44+/CD24low expressing breast cancer stem cells, BrCSC, were enriched followed by paclitaxel treatment, whereas the combination of anti-DLL4 and paclitaxel reversed paclitaxel-induced increase in this cell population. Further analysis indicated that blocking DLL4 signaling in tumor cells by anti-human DLL4 delayed tumor recurrence and decreased ESA+/CD44+/CD24low expressing BrCSC fraction and tumorigenic potential, whereas blocking DLL4 in host stroma and endothelial cells by anti-mouse DLL4 interfered with angiogenesis. The combination of both antibodies produced an additive effect. Our findings provide a rationale for targeting cancer stem cells and tumor vasculature through inhibition of the DLL4/Notch signaling for TNBC treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 15.

Targeting Cancer Stem Cells and Vasculature by a Novel Anti-Delta-Like 4 Ligand (DLL4) Antibody for Treatment of Triple Negative Breast Cancer.

Abstract Triple negative (ER-, PR- Her2-) breast cancer accounts for 10% of all types of breast cancer and is known to particularly aggressive and refractory to current therapies. Chemotherapeutic agents, such as taxanes, are currently the only treatment option for this type of breast cancer, however, these treatments often result in high rates of local and systemic relapse. It has been suggested that cancer stem cells drive tumor growth and progression and are preferentially resistant to many current therapies. Delta-like 4 ligand (DLL4) is an important component of the Notch signaling pathway which is known to mediate stem cell self-renewal and vascular development. We hypothesized that targeting cancer stem cells and the tumor vasculature by interfering with the DLL4/Notch pathway will improve treatment outcome. We developed anti-DLL4 antibodies that recognize either the human or murine protein and have potent binding and antagonist activities. We have used these antibodies to investigate the role of DLL4 in triple negative breast cancer and to probe the mechanism in tumor and stromal cells in xenograft models derived from primary breast tumors. These studies showed that anti-DLL4 was efficacious as a single agent and in combination with paclitaxel (Taxol) against triple negative breast tumors including a tumor that developed paclitaxel resistance. Gene expression analysis showed that anti-DLL4 affected vascular-related genes in the stroma and Notch target genes in the tumor and stroma. Furthermore, inclusion of anti-DLL4 delayed breast tumor recurrence following termination of paclitaxel treatment. A tumorigenicity study indicated that treatment with anti-DLL4 decreased cancer stem cell frequency as measured by in vivo limiting dilution assay, whereas paclitaxel alone was ineffective. The combination of anti-DLL4 and paclitaxel further decreased cancer stem cell frequency compared to single agents. Our findings provide a rationale for targeting cancer stem cells and tumor vasculature through inhibition of the DLL4/Notch signaling for breast cancer treatment. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5071.