Search

BackgroundAlthough immunotherapy can induce durable anti-tumor response in multiple cancers, immune checkpoint blockade (ICB) therapy resistance in ovarian cancer and melanoma remains problematic. Here, we report that tumor cell-intrinsic mTORC1 regulates ICB response through mTORC1 defining subunit Raptor (Rptor) by modulating interferon-gamma (IFNg) resistance and tumor-initiating cell (TIC) virulence.MethodsWe knocked down two distinct mTORC1 signaling components: Rptor (Rptorlo, aids in mTORC1 assembly) and Lamtor1 (Ltor1lo, docks mTORC1 on lysosomes) in murine ovarian cancer ID8agg and melanoma B16 cells. PD-L1 was CRISPR knocked out in B16 and human ovarian cancer line ES2. Mice with tumors were treated with a-PD-L1± a-CD8 antibody. TICs were estimated by flow-cytometry.1ResultsRptorlo B16 and ID8agg, but not Ltor1lo B16 tumors grew slower and were a-PD-L1 responsive unlike control (ctrl) in WT mice. We noted that ctrl and Rptorlo B16 and ID8agg cells expressed similar surface PD-L1 in vitro. Thus, Rptor suppresses a-PD-L1 response in ICB-resistant tumors. Tumor immune analysis revealed increased CD8+ T cell% and a trend to increased IFNg+CD8+ T cells in a-PD-L1 treated Rptorlo, but not ctrl B16. Rptorlo a-PD-L1 efficacy was lost with a-CD8 and in IFNg knockout mice. In vitro, IFNg suppressed Rptorlo ID8agg proliferation, unlike ctrl. These data suggested that lack of Rptor makes tumors ICB responsive, possibly by making tumors IFNg-sensitive and increasing IFNg+CD8+ T cells. Further, tumor and draining lymph node (DLN) TCF1+PD-1+ T cell stem cells (critical for aPD-L1/PD-1 success2 3) were significantly higher in a-PD-L1 treated Rptorlo tumors. Thus, tumor Rptor status could regulate tumor microenvironment and distal DLN immune landscape on a-PD-L1 treatment.We previously published that mTORC1 promotes PD-L1-dependent tumor proliferation, TIC virulence1 4 PD-L1KO B16 and ES2 cells expressed similar total Rptor protein. However, lower levels of Rptor were loaded in mTOR complex in absence of PD-L1, as assessed by a-mTOR immunoprecipitation, suggesting that pro-tumorigenic Rptor functions were downstream of, and dependent on PD-L1. Successful Rptorlo aPD-L1 treatment reduced TIC in vivo, an effect reversed in absence of CD8+ T cells or host IFNg. Inhibiting ID8agg mTORC1 with rapamycin reduced stemness genes oct4, nanog expression by QPCR. Further, ID8agg Rptorlo TIC formed significantly smaller tumors versus ctrl TIC in immune-compromised NSG mice, confirming their reduced virulence. Rptor, but not Ltor1, expression inversely correlated with tumor CD8+ infiltrate in IMvigor210 trial, and strongly with TIC gene signature in ovarian cancer patients.5 6ConclusionsTumor-cell intrinsic Rptor modulates ICB resistance, IFNg responsiveness, immune microenvironment, and TIC virulence.AcknowledgementsN/ATrial RegistrationN/AReferencesGupta HB, et al. Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer. Signal Transduct Target Ther 2016;1,Article number:16030.Im SJ, et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 2016;537:417–421.Dammeijer F, et al. The PD-1/PD-L1-checkpoint restrains T cell immunity in tumor-draining lymph nodes. Cancer Cell 2020;38:685–700.Clark CA, et al. Tumor-intrinsic PD-L1 signals regulate cell growth, pathogenesis, and autophagy in ovarian cancer and melanoma. Cancer Res 2016;76:6964–6974.Smith BA, et al. A human adult stem cell signature marks aggressive variants across epithelial cancers. Cell Rep 2018;24:3353–3366.Hoffman-Censits JH, et al. IMvigor 210, a phase II trial of atezolizumab (MPDL3280A) in platinum-treated locally advanced or metastatic urothelial carcinoma (mUC). J Clin Oncol 2016;34, no.2_suppl:355–355.

Summary: Colorectal cancer (CRC) is one of the most common cancers worldwide, in which adenomatous polyposis coli (APC) mutations are frequently and uniquely observed. Here we find that cis-HOX (circular RNA stabilizing HOXC10) is robustly expressed in colorectal tumor-initiating cells (TICs). cis-HOX knockout decreases colorectal TIC numbers and impairs the self-renewal, tumorigenesis, and metastatic capacities of TICs, whereas cis-HOX overexpression drives colorectal TIC self-renewal and metastasis. Mechanistically, cis-HOX binds to HOXC10 mRNA to attenuate its decay through blocking the K-homology splicing regulatory protein (KSRP)-binding sequence of HOXC10 3′ UTR. HOXC10 is highly expressed in colorectal tumors and TICs and triggers Wnt/β-catenin activation by activating FZD3 expression. HOXC10 inhibitor salinomycin exerts efficient therapeutic effects in APC-wild-type colorectal tumors, but not in tumors with APC nonsense mutations. Therefore, the cis-HOX-HOXC10 pathway drives colorectal tumorigenesis, stemness, and metastasis and serves as a potential therapeutic target for APC-wild-type colorectal tumors.

Osteosarcoma (OS) is the most frequent primary bone cancer in children and adolescents and the third most frequent in adults. Many inherited germline mutations are responsible for syndromes that predispose to osteosarcomas including Li Fraumeni syndrome, retinoblastoma syndrome, Werner syndrome, Bloom syndrome or Diamond–Blackfan anemia. TP53 is the most frequently altered gene in osteosarcoma. Among other genes mutated in more than 10% of OS cases, c-Myc plays a role in OS development and promotes cell invasion by activating MEK–ERK pathways. Several genomic studies showed frequent alterations in the RB gene in pediatric OS patients. Osteosarcoma driver mutations have been reported in NOTCH1, FOS, NF2, WIF1, BRCA2, APC, PTCH1 and PRKAR1A genes. Some miRNAs such as miR-21, -34a, -143, -148a, -195a, -199a-3p and -382 regulate the pathogenic activity of MAPK and PI3K/Akt-signaling pathways in osteosarcoma. CD133+ osteosarcoma cells have been shown to exhibit stem-like gene expression and can be tumor-initiating cells and play a role in metastasis and development of drug resistance. Although currently osteosarcoma treatment is based on adriamycin chemoregimens and surgery, there are several potential targeted therapies in development. First of all, activity and safety of cabozantinib in osteosarcoma were studied, as well as sorafenib and pazopanib. Finally, novel bifunctional molecules, of potential imaging and osteosarcoma targeting applications may be used in the future.

Lung cancer is the main cause of cancer death worldwide. Rapid accurate diagnosis, recognition of risk factors and improvement of treatment efficacy represent the main challenges. An advanced stage of the disease at the time of diagnosis, observed in the majority of cases, makes the introduction of radical treatment impossible or ineffective. Immunotherapy was a breakthrough in achieving long-term survival in recent years. The reason for developing this type of treatment is to know the interaction between the host cells and tumor cells. Cancer stem cells theory is increasingly gaining greater significance in the world. The biological heterogeneity of lung cancer may be due to the presence of a small percentage of cancer stem cells (CSCs). CSCs are the results of genetic and epigenetic changes in normal stem cells, progenitor cells or differentiated cells. CSCs are functionally defined by their unlimited self-renewal capacity, multiple differentiation and their ability to imitate tumors. It is believed that CSCs determine unrestricted growth of tumors and their different morphology. Their ability to self-renew can be the cause of relapses even after long periods of remission. CSCs reside in niches, where they receive signals for differentiation and proliferation process. The identification of CSCs is based on the presence of specific molecules (CD133, CD44, CD90, ALDH, EpCAM). An important feature of CSCs is their resistance to conventional cancer treatment: radio therapy and chemotherapy. Presumably, CSCs are responsible for the synthesis of immunosuppressive particles, and recruiting other molecules, which have immunosuppressive properties. The paper presents the current state of knowledge on CSCs in lung cancer detailing adenocarcinoma.

// Xin-Xing Zhu 1, 2, * , Ya-Wei Yan 1, 2, * , Chun-Zhi Ai 1 , Shan Jiang 1 , Shan-Shan Xu 1 , Min Niu 3 , Xiang-Zhen Wang 4 , Gen-Shen Zhong 5 , Xi-Feng Lu 6 , Yu Xue 7 , Shaoqi Tian 8 , Guangyao Li 9 , Shaojun Tang 10 , Yi-Zhou Jiang 1 1 Institute for Advanced Study, Shenzhen University, Shenzhen, Guangdong, China 2 Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong, College of Optoelectronic Engineering, Shenzhen University, Shenzhen, Guangdong, China 3 Department of Statics, University of Wisconsin-Madison, Madison, WI, USA 4 Maternal and Child Health Hospital of Nanshan District, Shenzhen, Guangdong, China 5 The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, China 6 Department of Physiology, Center for Diabetes, Obesity and Metabolism, Shenzhen University, Shenzhen, Guangdong, China 7 Minnan Normal University, Zhangzhou, Fujian, China 8 The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China 9 Department of Health Outcomes and Policy, College of Medicine, University of Florida, Gainesville, FL, USA 10 Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington, DC, USA * These authors contributed equally to this work Correspondence to: Yi-Zhou Jiang, email: jiangyz@szu.edu.cn Keywords: Jarid2, bladder tumors, tumor-initiating cells, p16, histone modification Received: November 24, 2016 Accepted: February 07, 2017 Published: February 20, 2017 ABSTRACT Bladder cancer is the most common urologic malignancy in China, with an increase of the incidence and mortality rates over past decades. Recent studies suggest that bladder tumors are maintained by a rare fraction of cells with stem cell proprieties. Targeting these bladder tumor initiating cell (TICs) population can overcome the drug-resistance of bladder cancer. However, the molecular and genetic mechanisms regulating TICs in bladder cancer remain poorly defined. Jarid2 is implicated in signaling pathways regulating cancer cell epithelial-mesenchymal transition, and stem cell maintenance. The goal of our study was to examine whether Jarid2 plays a role in the regulation of TICs in bladder cancer. We found that knockdown of Jarid2 was able to inhibit the invasive ability and sphere-forming capacity in bladder cancer cells. Moreover, knockdown of Jarid2 reduced the proportion of TICs and impaired the tumorigenicity of bladder cancer TICs in vivo . Conversely, ectopic overexpression of Jarid2 promoted the invasive ability and sphere-forming capacity in bladder cancer cells. Mechanistically, reduced Jarid2 expression led to the upregulation of p16 and H3K27me3 level at p16 promoter region. Collectively, we provided evidence that Jarid2 via modulation of p16 is a putative novel therapeutic target for treating malignant bladder cancer.

In article https://doi.org/10.1002/advs.201901728, Suling Liu and co‐workers report that the “decoy receptor” IL‐1 receptor 2 (IL1R2) is highly expressed on the most tumorigenic intermediate‐state breast tumor initiation cells (BTICs), which fall in between the epithelial‐like state and mesenchymal‐like state. IL‐1β in the tumor microenvironment activates the IL1R2 signaling pathway and then increases intermediate‐state BTIC self‐renewal and tumor progression, which can be specifically blocked by IL1R2 neutralizing antibody.

Tumor-initiating cells are a diminutive subpopulation of stem cells that have ability of long term self-renewal and generation of varied traits of tumor cell population. Understanding the concept of tumor-initiating cells may have a great implicative intimation for our comprehension of cancer pathobiology and for the delineation of new therapies directed towards these stem cells. The present review is an endeavor to conceptualize the role of tumor-initiating cells in the Squamous Cell Cancers (SCC) of head and neck, their role in tumorigenesis and the possible supplementary approach in the latest treatment modalities.

// Alice Nomura 1, 2 , Patricia Dauer 1, 2 , Vineet Gupta 1, 2 , Olivia McGinn 1 , Nivedita Arora 1 , Kaustav Majumdar 1 , Charles Uhlrich III 1 , Joseph Dalluge 3 , Vikas Dudeja 1, 2 , Ashok Saluja 1, 2 , Sulagna Banerjee 1, 2 1 Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, MN, USA 2 Division of Surgical Oncology, Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA 3 Department of Chemistry, Mass Spectrometry Laboratory, University of Minnesota, Minneapolis, MN, USA Correspondence to: Sulagna Banerjee, email: Sulagna.Banerjee@med.miami.edu Keywords: CD133, tumor initiating cells, metabolism, hypoxia, ROS Received: April 25, 2016 Accepted: July 10, 2016 Published: July 26, 2016 ABSTRACT Chemoresistance in pancreatic cancer has been attributed to tumor-initiating cells (TICs), a minor sub-population of tumor cells. However, the mechanism of chemo-resistance in these cells is still unclear. In the current study, immunohistochemical analysis of LSL-Kras G12D ; LSL-Trp53 R172H; PdxCre (KPC) murine tumors indicated that hypoxic regions developed through tumor progression. This hypoxic “niche” correlated with increased CD133 + population that had an increased HIF1A activity. Consistent with this observation, CD133 + cells had increased glucose uptake and activity of glycolytic pathway enzymes compared to CD133 − cells. Mass spectrometric analysis (UPLC-TQD) following metabolic labeling of CD133 + cells with [ 13 C]-U6 glucose confirmed this observation. Furthermore, although both populations had functionally active mitochondria, CD133 + cells had low mitochondrial complex I and complex IV activity and lesser accumulation of ROS in response to standard chemotherapeutic compounds like paclitaxel, 5FU and gemcitabine. CD133 + cells also showed increased resistance to all three chemotherapeutic compounds and treatment with Glut1 inhibitor (STF31) reversed this resistance, promoting apoptotic death in these cells similar to CD133 − cells. Our study indicates that the altered metabolic profile of CD133 + pancreatic TIC protects them against apoptosis, by reducing accumulation of ROS induced by standard chemotherapeutic agents, thereby confering chemoresistance. Since resistance to existing chemotherapy contributes to the poor prognosis in pancreatic cancer, our study paves the way for identifying novel therapeutic targets for managing chemoresistance and tumor recurrence in pancreatic cancer.

Ovarian cancer (OC) is a global health burden with the poorest 5-year survival rate of the gynecological malignancies. Disease recurrence is the major cause of morbidity and mortality of OC, likely driven by the survival of chemoresistant, self-renewing tumor-initiating cells (TICs). The TIC population in OC acquires features to survive cellular stress and avoid apoptosis but these can also be targeted as vulnerabilities specific to the TIC population of OC to prevent recurrence. To reveal these vulnerabilities, a high-throughput drug screen was performed to identify drugs that showed increased efficacy against OC cells grown in TIC-enriching spheroid (TES) conditions compared to adherently grown cells. Four drugs were selected for further investigation. Disulfiram, Bardoxolone Methyl, Elesclomol and Salinomycin were tested in vitro to confirm the effects on viability of OC cells in adherent or TES conditions. The drugs' efficacy against sphere formation and expression of markers of stemness as high ALDH activity and CD133 expression (ALDH+CD133+) as single agents or in combination with carboplatin was also investigated in vitro. Disulfiram showed the greatest efficacy against spheroid viability and decreased the ALDH+CD133+ population of several OC cell lines. This effect was enhanced when combined with carboplatin. Bardoxolone Methyl, Elesclomol and Salinomycin showed similar efficacy against cell viability in OC cells grown adherently or in TES conditions; Elesclomol significantly inhibited the ALDH+CD133+ population of the OC cells which was again enhanced in combination with carboplatin. RNAseq analysis revealed a strong enrichment of genes involved in oxidative phosphorylation and reactive oxygen species (ROS) pathways in TES conditions compared to adherent conditions. The drugs were investigated for their ability to promote oxidative stress and OC cells were measured for accumulation of intracellular ROS and mitochondrial superoxide after exposure to the drugs. OC cells grown in TES conditions had higher basal intracellular ROS levels than adherently grown cells and the level of ROS was significantly enhanced in TES cells treated with Elesclomol or Disulfiram but no differences were seen in adherently grown cells. Salinomycin and Bardoxolone Methyl increased mitochondrial superoxide accumulation in some OC cell lines under TES conditions. In a model of OC relapse in vitro, Disulfiram and Elesclomol following carboplatin treatment significantly increased cell death compared to carboplatin alone. Disulfiram and Salinomycin were incorporated into a mouse model to test their ability to prevent OC relapse after chemotherapy in vivo. These results demonstrate that targeting key pathways mediating increased oxidative stress in TICs can eliminate this population and provide a means to prevent OC recurrence. Citation Format: Brittney S. Harrington, Christina M. Annunziata. Drugs targeting ovarian cancer tumor-initiating cells enhance oxidative stress and prevent disease recurrence [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3582.

In recent years, immune manipulation for cancer treatment, including breast cancer, has been increasingly gaining consent, and many attempts have been made, mainly by either strengthening the immune response (IR) or by inhibiting immune evasion. Therefore, elucidating the related mechanisms is of importance due to the potential to improve the management of cancer patients by immunotherapy. This review article summarized some recent experimental studies, which have discovered novel alterations of signaling pathways related to the immune system in breast cancer. These altered signaling pathways have been grouped according to the general biological mechanism involved: tumor-initiating cells (TICs), cancer stem cells (CSCs), immune evasion, tumor growth and progression, prediction of clinical outcome and prediction of response, or resistance to chemotherapy. These altered pathways related to the immune system open clinical opportunities for the prognosis or treatment of patients. Many of these pathways are related to the origin of breast cancer and immune evasion. We recommended development of new drugs which act on these molecular pathways, and the designing of clinical trials to be carried out mainly in breast cancer patients who required adjuvant treatment.

Resistance to chemotherapy and cancer relapse are major clinical challenges attributed to a sub population of cancer stem cells (CSCs). The concept of CSCs has been the subject of intense research by the oncology community since evidence for their existence was first published over twenty years ago. Emerging data indicates that they are also able to evade novel therapies such as targeted agents, immunotherapies and anti-angiogenics. The inability to appropriately identify and isolate CSCs is a major hindrance to the field and novel technologies are now being utilized. Agents that target CSC-associated cell surface receptors and signaling pathways have generated promising pre-clinical results and are now entering clinical trial. Here we discuss and evaluate current therapeutic strategies to target CSCs.

Background Tumor initiating cells are a small subset of cancer cells responsible for tumor growth and recurrence. The status of tumor initiating cells was measured using the surface markers CD133 (prominin-1) and ESA (epithelial-specific antigen). The aims of this study were to investigate the significance of CD133+/ESA+ cells in mesenteric venous blood (MVB) and tumor mass (TM) for overall survival (OS) and disease-free survival (DFS) in colorectal cancer (CRC) patients undergoing curative resection. Materials and methods A total of 229 CRC patients undergoing curative resection were prospectively enrolled in the study. Using CD133 and ESA as surface markers, CD133+/ESA+ cells were enumerated from MVB and TM using flow cytometry. Results We analyzed the presence of CD133+/ESA+ cells in TM from 158 patients and found no correlation to patient DFS, OS, or clinical stage. In 135 patients, an analysis of CD133+/ESA+ cells in MVB showed an inverse correlation with both DFS and OS (P = 0.014 and P = 0.008, respectively). It exhibited an increase-then-decrease pattern with the peak in stage II patients. A multivariate Cox analysis demonstrated that the status of CD133+/ESA+ cells in MVB, but not the TM, was a significant prognostic factor for DFS and OS (P = 0.003 and P = 0.011, respectively). Conclusions The status of CD133+/ESA+ cells in MVB, but not in TM, could be a useful indicator for predicting tumor recurrence and a prognostic marker for CRC patients.

Objective To investigate the influence of CD133 + expression on patients' survival and resistance of CD133 + cells to anti-tumor agents in gastric cancer (GC). Methods Influence of CD133 expression on prognosis was analyzed employing samples from patients with GC. GC cell lines were utilized to separate CD133 + and CD133 − subpopulations by immunomagnetic separation and to analyze the biological features of two subpopulations in vitro and in vivo , especially in resistant to anti-tumor reagents and its apoptotic mechanism. Results The lower CD133 + group showed a significantly better survival compared with the higher CD133 + group. The highest content of CD133 + subpopulations for KATO-III cells had stronger proliferative ability than CD133 − subpopulations. A single CD133 + cell was capable of generating new cell colony and the tumorigenicity rate in nude mice was 100% for CD133 + clonal spheres or for CD133 + cells, but 0% for CD133 − cells. Furthermore, the higher expression levels of Oct-4, Sox-2, Musashi-1 and ABCG2 in CD133 + clonal spheres were identified compared with CD133 + cells or CD133 − cells. Under the treatment of anti-tumor reagents, CD133 + cells had lower suppression rates compared with CD133 − cells while lower level of Bcl-2 and higher level of Bax were found in CD133 + cells compared with CD133 − cells. Conclusions The patients with lower CD133 + expression had a better survival. Enriched CD133 + cells in clonal sphere shared the ability to be self-renewable, proliferative, tumorigenic and resistant to anti-tumor agents as probably regulated by Bcl-2 and Bax.

Mucoepidermoid carcinoma (MEC) is the most frequent malignant salivary gland cancer. Response to chemoradiotherapy is modest, and therefore radical surgery remains the standard-of-care. Emerging evidence suggests that Interleukin (IL)-6 signaling correlates with the survival of cancer stem cells and resistance to therapy. Here, we investigated whether inhibition of IL-6 receptor (IL-6R) signaling with tocilizumab (humanized anti-human IL-6R antibody) sensitizes MEC to chemotherapy using human mucoepidermoid carcinoma cell lines (UM-HMC) and correspondent xenograft models. In vitro, we observed that tocilizumab inhibited STAT3 phosphorylation but had no measurable effect in MEC cell viability (UM-HMC-1,-3A,-3B). In contrast, the anti-tumor effect of single agent tocilizumab on MEC xenografts was comparable to paclitaxel or cisplatin. Combination of tocilizumab with cisplatin or paclitaxel enhanced the inhibitory effect of chemotherapy on xenograft growth (P < 0.05), time to failure (P < 0.01), decreased vascular endothelial growth factor (VEGF) expression and tumor microvessel density (P < 0.05) without added systemic toxicities. Notably, tocilizumab decreased the fraction of MEC cancer stem cells (ALDH(high)CD44(high)) in vitro, and prevented paclitaxel-induced increase in the fraction of cancer stem cells in vivo (P < 0.05). Collectively, these findings demonstrate that tocilizumab enhances the anti-tumor effect of conventional chemotherapy in preclinical models of mucoepidermoid carcinoma, and suggest that patients might benefit from combination therapy with an inhibitor of IL-6R signaling and chemotherapeutic agent such as paclitaxel.

Medulloblastoma represents the most common childhood brain tumor. Despite aggressive multimodal therapy, a significant proportion of surviving patients suffer from severe treatment-related side effects, including tumor relapse. Thus, there is an urgent need for novel therapeutic modalities that can improve patient survival while minimizing tumor recurrence. Our recent study identified GNAS as a novel tumor-suppressor gene in Sonic hedgehog-driven medulloblastomas (Ref.1). Low expression or mutation of GNAS was tightly correlated with poor prognosis of Sonic hedgehog-group tumors and their resistance to the treatment of Sonic hedgehog signaling inhibitors alone. Ablation of the single GNAS gene in anatomically-distinct progenitors in the ventricular zone of the cerebellum and dorsal brainstem is sufficient to induce medulloblastoma formation, recapitulating their human counterparts. Gsα activation suppresses Sonic hedgehog signaling by regulating both the cAMP-dependent PKA pathway and ciliary trafficking of Hedgehog pathway components. Elevation of a Gsα effector, cAMP, effectively inhibits tumor growth in GNAS mutants. Strikingly, we find that in the drug-resistant tumor lesion and recurrent tumors after radiation therapy, there is an increase of Olig2 expression and Olig2+ progenitor cells. High levels of Olig2 are correlated with poor prognosis of medulloblastomas in human patients. We show that elimination of the mitotic Olig2-expressing cells blocks tumor progression in Olig2-TK transgenic mice. In addition, cell type-specific deletion of Olig2 halts tumor progression. Moreover, we find that Olig2 activates gene regulatory networks inferred for tumor cell stemness and regulates chromatin accessibility of oncogenic factors by altering epigenome landscapes. Furthermore, our single cell analyses reveal that Olig2-expressing progenitors are the distinct tumor-initiating cells during the onset of primary and recurrent medulloblastoma, highlighting potential therapeutic avenues for treating recurrent medulloblastomas by targeting Olig2-expressing progenitors. Ref.1: He, X. et al., “The G protein-alpha subunit Ga is a tumor suppressor in Sonic hedgehog-driven medulloblastoma”. Nat Med 20: 1035–1042.

Cancer stem cells (CSCs) with stem-cell properties are regarded as tumor initiating cells. Sharing stem-cell properties, circulating tumor cells (CTCs) are responsible for the development of metastasis, which significant affects CTC analysis in clinical practice. Due to their extremely low occurrence in blood, however, it is challenging to enumerate and analyze CTCs. Nanotechnology is able to address the problems of insufficient capture efficiency and low purity of CTCs owing to the unique structural and functional properties of nanomaterials, showing strong promise for CTC isolation and detection. In this review, we discuss the role of stem-like CTCs in metastases, provide insight into recent progress in CTC isolation and detection approaches using various nanoplatforms, and highlight the role of nanotechnology in the advancement of CTC research.

Encouraging survival was observed in single arm and randomized phase 2 trials of patient-specific dendritic cell vaccines presenting autologous tumor antigens from autologous cancer cells that were derived from surgically resected metastases whose cells were self-renewing in vitro. Based on most advanced clinical stage and extent of tumor at the time of treatment, survival was best in patients classified as recurrent stage 3 without measurable disease. Next best was in stage 4 without measurable disease, and the worst survival was for measurable stage 4 disease. In this study, the survival of these patients was compared to the best contemporary controls that were gleaned from the clinical trial literature. The most comparable controls typically were from clinical trials testing other immunotherapy approaches. Even though contemporary controls typically had better prognostic features, median and/or long-term survival was consistently better in patients treated with this dendritic cell vaccine, except when compared to anti-programmed death molecule 1 (anti-PD-1). The clinical benefit of this patient-specific vaccine appears superior to a number of other immunotherapy approaches, but it is more complex to deliver than anti-PD-1 while equally effective. However, there is a strong rationale for combining such a product with anti-PD-1 in the treatment of patients with metastatic melanoma.

In the version of this article originally published, there is an error in Fig. 5a. Originally, 'MAT2A' appeared between 'Methionine' and 'Homocysteine'. 'MAT2A' should have been 'MTR'. The error has been corrected in the PDF and HTML versions of this article.

Background Recently, tumor initiating cells (TICs), which possess self-renewal and other stem cell properties, are regarded as the cause of tumor initiation, recurrence and metastasis. The isolation and identification of TICs could help to develop novel therapeutic strategies. Methods In this study, we isolated spheroid cells from human renal cell carcinoma (RCC) cell line SN12C in stem cell-conditioned medium. The stemness characteristics of spheroid cells, including tumorigenicity, self-renewal, proliferation and aldehyde dehydrogenase (ALDH) activity were evaluated; the expression levels of stemness genes and related proteins were assessed. Furthermore, study examined the differentiation of TICs into endothelial cells and the relationship between TICs and EMT. Results Our data demonstrated that spheroid cells cultured in defined serum-free medium possessed TIC properties, such as high tumorigenic capacity, upregulation of TIC-related genes and proteins, persistent self-renewal and extensive proliferation. Furthermore, spheroid cells were more aggressive in growth, invasion, scratch recovery, clonogenic survival and high aldehyde dehydrogenase (ALDH) activity. Interestingly, a marked increase in tumor vascularity compared to adherent tumors in vivo, and spheroid cells can differentiate into functional endothelial-like cells in vitro suggesting a role of tumor initiating cells in tumor angiogenesis. The spheroid cells also demonstrated down-regulated E-cadherin and up-regulated Vimentin expression, which is the typical phenotype of EMT. Conclusions These results suggest that spheroid cells with tumor initiating cells-like characteristics contributed to tumor generation, progression, high tumorigenicity, pro-angiogenic capability and relationship with EMT. Further experiments using more refined selection criteria such as a combination of two or multiple markers would be useful to specifically identify and purify TICs.

Background CD105 was postulated as a renal cell carcinoma (RCC) stem cell marker, and CD133 as a putative RCC progenitor. Hypoxia, a natural microenvironment that prevails in tumors, was also incorporated into the study, especially in terms of the promotion of hypothetical stem-like cell properties. Methods Within this study, we verify the existence of CD105+ and CD133+ populations in selected papillary subtype RCC (pRCC) cell lines. Both populations were analyzed for correlation with stem-like cell properties, such as stemness gene expression, and sphere and colony formation. For the preliminary analysis, several RCC cell lines were chosen (786-O, SMKT-R2, Caki-2, 796-P, ACHN, RCC6) and the control was human kidney cancer stem cells (HKCSC) and renal cells of embryonic origin (ASE-5063). Four cell lines were chosen for further investigation: Caki-2 (one of the highest numbers of CD105+ cells; primary origin), ACHN (a low number of CD105+ cells; metastatic origin), HKCSC (putative positive control), and ASE-5063 (additional control). Results In 769-P and RCC6, we could not detect a CD105+ population. Hypoxia variously affects pRCC cell growth, and mainly diminishes the stem-like properties of cells. Furthermore, we could not observe the correlation of CD105 and/or CD133 expression with the enhancement of stem-like properties. Conclusions Based on this analysis, CD105/CD133 cannot be validated as cancer stem cell markers of pRCC cell lines.

Recent data suggest the existence of a subset of breast cancer cells variously termed cancer stem cells, tumor-initiating, or tumor-propagating cells, that are capable of self-renewal and of regenerating tumors upon transplantation that are biologically consistent with the tumor of origin. These cells appear to be intrinsically resistant to systemic chemo- and radiation therapies and may therefore be responsible for treatment resistance, and disease recurrence. Several signal transduction networks have been implicated in normal and malignant stem cell self-renewal. These include those of the Hedgehog, Notch, Wnt, EGF, FGF families of ligands. Antagonists of these networks have become attractive targeted therapeutic agents. In this study, we evaluated two different Hedgehog signaling antagonists, one targeting Smoothened (the main membrane effector of activated signaling) and one targeting GLI1/2 (the two transcription factors mediating ligand response), for their ability to shrink patient-derived xenograft tumors and to affect the number or function of breast tumor-initiating cells in vivo. Both antagonists showed little effect as single agents, but could augment tumor shrinkage by docetaxel. However, these effects were only observed in those models showing evidence of canonical SMO/GLI-mediated signaling. In dilutional transplantation assays, both SMO or GLI targeted agents have a biphasic effect on the behavior of the tumor-initiating population such that large cell numbers yielded few tumors while intermediate cell numbers yielded tumors at a comparable rate as controls. These data suggest that combination therapy alters the functional state of stem cells in the context of larger cell numbers rather than targeting the tumor-initiating cell directly. These data therefore have significant relevance for the interpretation of ongoing clinical trials of hedgehog signaling inhibitors in solid tumors, including breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-04-09.

Recently, a subpopulation of cells, termed tumor-initiating cells or tumor stem cells (TSC), has been identified in many different types of solid tumors. These TSC, which are typically more resistant to chemotherapy and radiation compared to other tumor cells, have properties similar to normal stem cells including multipotency and the ability to self-renew, proliferate, and maintain the neoplastic clone. Much of the research on TSC has focused on adult cancers. With considerable differences in tumor biology between adult and pediatric cancers, there may be significant differences in the presence, function and behavior of TSC in pediatric malignancies. We discuss what is currently known about pediatric solid TSC with specific focus on TSC markers, tumor microenvironment, signaling pathways, therapeutic resistance and potential future therapies to target pediatric TSC.

Introduction p300 is a well-known coactivator of the androgen receptor (AR) and has been shown to play an important role in prostate cancer (PCa). The expression of p300 has been correlated to tumor volume and PCa progression. Therefore, we hypothesize that p300 may play an important role in tumor-initiating cells and therapy resistance. Due to its multifunctional role p300 may serve as a promising new therapeutic target for treatment of PCa. Ultimately, it is our aim to find new innovative therapeutic targets for castration resistant PCa. Material & Methods The tumor-initiating capacity of the AR-negative PCa cell lines PC3 and Du145, as well as primary prostate epithelial cells was characterized by seeding a limiting number of cells per flask. Colony formation efficiency, colony type and detailed morphological information about each colony were determined by an automated pipeline that we have developed. Stable cell lines with doxycycline inducible p300 sh RNAs were generated by lentiviral transduction. Knockdown of p300 was verified by Western Blot and reduced p300 activity was confirmed by measuring histone h3 acetylation. Results In concordance with the literature we identified three colony types (holo-, mero- and paraclones) in PC3 and Du145 cell lines as well as primary PCa cells. Serial clonogenic assays confirmed in both cell lines that holoclones show the highest colony formation potential and maintain their tumor-initiating capacity over numerous rounds. In PC3 we detected 10% and in Du145 30% holoclones. Under optimal growth conditions p300 was detected in all colony types, however no differences in protein expression of p300 as well as on mRNA level were observed. Knockdown of p300 did not alter colony formation efficiency or the relative distribution of colony types. Conclusion Taken together, we confirmed the presence of tumor-initiating holoclones in PCa cell lines and primary prostate epithelial cells and established stable cell lines with inducible knockdown of p300. In contrast to several other types of malignancies, p300 has no specific role in regulation of stemness in our PCa models at the tested conditions. As a next step we will determine the effects of p300 knockdown during chemotherapy and radiation therapy to evaluate if p300 depletion may enhance the treatment efficacy and which role p300 plays in therapy resistance. Citation Format: Martina Gruber, Florian Handle, Zoran Culig. Transcriptional integrator p300 in human prostate tumor-initiating cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2001.

Bisher galten alle Tumorzellen innerhalb eines Tumors als grundsatzlich gleich maligne. Es mehren sich nun Hinweise, dass Tumoren auch hierarchisch gegliedert sein konnen. Danach befinden sich im Tumor einige wenige, sich selbst erneuernde und dadurch tumorbildende Tumorstammzellen (TSZ), welche die Quelle von differenzierteren Tumorzellen sind. TSZ konnen ihren Ursprung zum einen in Gewebestammzellen, zum anderen aber auch in schon differenzierten Gewebezellen haben. Der Nachweis von TSZ in einer Tumorart kann zu einer Anderung in der klinischen Vorgehensweise fuhren. Es werden nicht mehr die zahlenmasig uberwiegenden differenzierten Tumorzellen fur die Prognose, die Patientenstratifizierung und die Beurteilung des Therapieansprechens, einer minimalen Resterkrankung oder eines Rezidivs als ausschlaggebend betrachtet, sondern die Zahl, die Funktionsfahigkeit und das Genexpressionsmuster der wenigen TSZ in Primartumor und Metastasen. Ein Tumor mit TSZ wird nach dem TSZ-Modell nur dann erfolgreich therapiert werden konnen, wenn auch die vergleichsweise therapieresistenten TSZ abgetotet oder differenziert werden. Trotz Kontroversen, die sich an der Definition von TSZ und deren Nachweismethoden entzundet haben, konnte das TSZ-Konzept zu verbesserten prognostischen und therapeutischen Verfahren in der Onkologie fuhren.

Active immunotherapy of cancer is a promising treatment modality by inducing long lived tumor reactive immune effector cells. Several vaccine trials have indicated that its effectiveness is probably best when the tumor burden is low. An attractive population of cells to target by this approach may be tumor initiating cells (TICs). Recent research suggests that such types of cells may be precursors to cancer possibly giving rise to metastatic disease. Although more work is being done to characterize appropriate phenotypic and functional markers, this population of cells would make an ideal target for active immunotherapy in high risk patients, so as to achieve remission over much longer periods of time. This review gives an overview of the potential of immunotherapy and how it may target TICs as a potential treatment option for cancer patients.

// Donatella Malanga 1 , Carmela De Marco 1, 2 , Ilaria Guerriero 2 , Fabiana Colelli 2 , Nicola Rinaldo 2 , Marianna Scrima 1, 2 , Teresa Mirante 3 , Claudia De Vitis 7 , Pietro Zoppoli 2 , Michele Ceccarelli 1, 4 , Miriam Riccardi 1, 2 , Maria Ravo 5 , Alessandro Weisz 5 , Antonella Federico 6 , Renato Franco 7 , Gaetano Rocco 7 , Rita Mancini 8 , Antonia Rizzuto 3 , Elio Gulletta 9 , Gennaro Ciliberto 7 , Giuseppe Viglietto 1, 2 1 Dipartimento di Medicina Sperimentale e Clinica, Universita Magna Graecia, Catanzaro, Italy 2 Biogem scarl, Istituto di Ricerche Genetiche, Ariano Irpino (Avellino), Italy 3 Dipartimento di Scienze Mediche e Chirurgiche, Universita Magna Graecia, Catanzaro, Italy 4 Dipartimento di Scienze e Tecnologie, Universita del Sannio, Benevento, Italy 5 Dipartimento di Medicina e Chirurgia, Universita di Salerno, Baronissi, Italy 6 Dipartimento di Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita Federico II, Napoli, Italy 7 IRCCS Istituto Nazionale Tumori Fondazione G. Pascale, Napoli, Italy 8 Dipartimento di Medicina Clinica e Molecolare, Universita di Roma “La Sapienza” Ospedale S. Andrea, Roma, Italy 9 Dipartimento di Scienze della Salute, Universita Magna Graecia, Catanzaro, Italy Correspondence to: Giuseppe Viglietto, e-mail: viglietto@unicz.it Keywords: NSCLC, tumor initiating cells, Akt1, IL-6, STAT3 Received: June 15, 2015 Accepted: September 09, 2015 Published: October 13, 2015 ABSTRACT Here we report that the PI3K/Akt1/IL-6/STAT3 signalling pathway regulates generation and stem cell-like properties of Non-Small Cell Lung Cancer (NSCLC) tumor initiating cells (TICs). Mutant Akt1, mutant PIK3CA or PTEN loss enhances formation of lung cancer spheroids (LCS), self-renewal, expression of stemness markers and tumorigenic potential of human immortalized bronchial cells (BEAS-2B) whereas Akt inhibition suppresses these activities in established (NCI-H460) and primary NSCLC cells. Matched microarray analysis of Akt1-interfered cells and LCSs identified IL-6 as a critical target of Akt signalling in NSCLC TICs. Accordingly, suppression of Akt in NSCLC cells decreases IL-6 levels, phosphorylation of IkK and IkB, NF-kB transcriptional activity, phosphorylation and transcriptional activity of STAT3 whereas active Akt1 up-regulates them. Exposure of LCSs isolated from NSCLC cells to blocking anti-IL-6 mAbs, shRNA to IL-6 receptor or to STAT3 markedly reduces the capability to generate LCSs, to self-renew and to form tumors, whereas administration of IL-6 to Akt-interfered cells restores the capability to generate LCSs. Finally, immunohistochemical studies in NSCLC patients demonstrated a positive correlative trend between activated Akt, IL-6 expression and STAT3 phosphorylation ( n = 94; p < 0.05). In conclusion, our data indicate that aberrant Akt signalling contributes to maintaining stemness in lung cancer TICs through a NF-kB/IL-6/STAT3 pathway and provide novel potential therapeutic targets for eliminating these malignant cells in NSCLC.

The heterogeneous nature of prostate cancer tumors is thought to play an important role in the decreased effectiveness of existing therapies. Tumor initiating cells (TICs) are capable of self-renewal and comprise a subset of the tumor mass. These cells are proposed to drive the growth and metastasis of tumors, and are considered to be resistant to traditional cytotoxic and targeted therapies. Several studies have shown that NF-κB signaling is increased in recurrent prostate cancer and enriched in prostate TICs. We sought to determine the potential of an IKK/NF-κB-driven mechanism for inherent or acquired resistance by IKK-mediated control of a subset of prostate tumor initiating cells. These studies were performed by using established prostate cancer cell lines, murine prostate organoids, and a murine prostate cancer animal model. We have found that inhibition of IKKα and IKKβ, upstream regulators of noncanonical and canonical NF-κB signaling, block self-renewal of several PTEN-deficient prostate cancer cell lines. Furthermore, we have also found that IKK is important for tumorigenicity and stemness seen in prostate cancer cells as measured by colony formation and extreme limiting dilution assays. Loss of canonical NF-κB (p65/RelA) decreased stemness while loss of noncanonical did not alter tumorsphere formation. Interestingly, Pten-/- tumors with loss of Ikkα or Ikkβ displayed decreased levels of self-renewing cells as measured by CD49fhigh expression, a known prostate basal cell marker. Isolated murine Pten-/- cells were 2x more efficient than Pten-/-Ikkα-/- or Pten-/-Ikkβ-/- cells in forming prostate organoids suggesting that loss of Ikk decreased the number of self-renewing cells needed for formation. Taken together, we conclude that IKK-mediated signaling is important for maintenance of prostate tumor initiating cells and further studies will address whether IKK-mediated signaling provides a mechanism for evading current therapies. Note: This abstract was not presented at the meeting. Citation Format: Sara E. Conard, Aaron Ebbs, Albert S. Baldwin. IKK-mediated signaling controls prostate tumor initiating cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2877. doi:10.1158/1538-7445.AM2017-2877

Ductal carcinoma in situ (DCIS) is an early-stage form of breast cancer that accounts for over 20% of all breast cancers in the US. Therefore, prevention of DCIS is a major goal for reducing breast cancer incidence. However, the underlying molecular and pathological mechanisms of DCIS remain poorly understood. It is believed that tumor-initiating cells are formed at a very early stage of tumorigenesis, which then leads to the progression of DCIS. Our recent work that focused on tumor-initiating cells of DCIS revealed that the expression of miR29c in tumor-initiating cells was significantly down-regulated in DCIS cells compared to that in normal cells. Furthermore, we found that the ID2 gene is one of the targets of miR29c in tumor-initiating cells and that miR29c suppresses the ID2 gene by directly binding to the 3’-UTR sequence. ID2 is a well-known dedifferentiation factor in embryonic development, and the ID family is involved in progression of cancer by affecting cell differentiation and proliferation. We also found that ectopic expression of ID2 in premalignant cells accelerated tumor growth and promoted self-renewal of tumor-initiating cells in DCIS, suggesting that ID2 also controls cancer cell dedifferentiation and promotes tumor-initiating cells formation. These results indicate that the miR29c-ID2 axis plays a critical role in self-renewal of DICS in vivo and that ID2 is a potential biomarker for tumor-initiating cells in DCIS. ID2 is thought to sequester E-protein transcription factors and thus regulates a wide range of gene expression. Our data suggest that ID2 upregulates expression of several cancers stem cell genes including SOX2, which is a well- known self-renewal regulator of stem cells. ID2 also upregulates the fatty acid synthase gene (FASN), which promotes cancer cell proliferation and survival. We also found that FASN expression was significantly suppressed by pterostilbene, indicating potential utility of this natural compound for preventing DCIS formation. Taken together, these results suggest that miR29c-ID2 functions as master regulators in forming DCIS. ID2 promotes self-renewal of tumor-initiating cells by regulating expression of the SOX2 and FASN genes. Note: This abstract was not presented at the meeting. Citation Format: Yin Liu, Puspa R. Pandey, Sambad Sharma, Kerui Wu, Fei Xing, Kounosuke Watabe. Roles of miR29c-ID2 axis in tumor initiating cells of breast ductal carcinoma in situ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5748. doi:10.1158/1538-7445.AM2017-5748

Ovarian cancer is the most lethal gynecological cancer, with overall five-year survival for women with advanced disease being at only 25%. The current standard of care is treatment with a platinum-based chemotherapy drug. Unfortunately, a subpopulation of tumor cells often persists, contributing to platinum-based chemotherapy resistance and disease recurrence. In this study we investigated drugs to target these putative tumor-initiating cells (TICs), and explored the pathways of these drugs in both adherent proliferative cell culture conditions and non-adherent TIC-enriched cultures. We conducted a drug screen under both growth conditions, in order to identify compounds that are able to inhibit growth of TICs. Of the drugs identified, we focused further efforts on those involved with inhibiting the NF-kappaB pathway because prior studies have linked NF-kappaB activity with drug resistance and poor survival. Cell viability assays done with the four drugs, bardoxolone methyl, salinomycin, disulfiram, and elesclomol, show these drugs inhibit the growth of ovarian cancer cell lines both as TICs and in corresponding adherent cultures. Disulfiram showed preferential killing of TICs in some of the cell lines tested. All drugs showed some evidence for inhibiting NF-kappaB on Western blot, and ability to decrease CD133/ALDH double-positive TICs on flow cytometry. Carboplatin is known to kill proliferative ovarian cancer cells, and increase the relative percentage of CD133/ALDH positive TICs. Our ongoing studies will address combination of each drug with carboplatin, with the hypothesis that these drugs will increase in vivo efficacy by suppressing TICs, and thereby decrease recurrence of platinum-resistant ovarian cancer. Citation Format: Michelle K. Ozaki, Carrie D. House, Christina M. Annunziata. Identifying drugs that target ovarian cancer tumor initiating cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 112. doi:10.1158/1538-7445.AM2017-112

Improving screening and treatment options for patients with epithelial ovarian cancer has been a major challenge in cancer research. Development of novel diagnostic and therapeutic approaches, particularly for the most common subtype, high-grade serous ovarian cancer (HGSC), has been hampered by controversies over the origin of the disease and a lack of spontaneous HGSC models to resolve this controversy. Over long-term culture in our laboratory, an ovarian surface epithelial (OSE) cell line spontaneously transformed OSE (STOSE). The objective of this study was to determine if the STOSE cell line is a good model of HGSC. STOSE cells grow faster than early passage parental M0505 cells with a doubling time of 13 and 48 h, respectively. STOSE cells form colonies in soft agar, an activity for which M0505 cells have negligible capacity. Microarray analysis identified 1755 down-regulated genes and 1203 up-regulated genes in STOSE compared to M0505 cells, many associated with aberrant Wnt/β-catenin and Nf-κB signaling. Upregulation of Ccnd1 and loss of Cdkn2a in STOSE tumors is consistent with changes identified in human ovarian cancers by The Cancer Genome Atlas. Intraperitoneal injection of STOSE cells into severe combined immunodeficient and syngeneic FVB/N mice produced cytokeratin+, WT1+, inhibin−, and PAX8+ tumors, a histotype resembling human HGSC. Based on evidence that a SCA1+ stem cell-like population exists in M0505 cells, we examined a subpopulation of SCA1+ cells that is present in STOSE cells. Compared to SCA1− cells, SCA1+ STOSE cells have increased colony-forming capacity and form palpable tumors 8 days faster after intrabursal injection into FVB/N mice. This study has identified the STOSE cells as the first spontaneous murine model of HGSC and provides evidence for the OSE as a possible origin of HGSC. Furthermore, this model provides a novel opportunity to study how normal stem-like OSE cells may transform into tumor-initiating cells.

The goal of this review is summarizing current technologies developed as the in vitro prognostic/diagnostic systems that can rapidly separate and detect circulating tumor cells (CTCs) from cancer patient’s blood (1–10 CTCs of 1 billion red blood cells) by labeled and non-labeled method. The review is focused on three major areas of CTC research (1) Summary of previous research on capturing of CTCs, (2) New development of the in vitro prognostic diagnosis system of cancer that is capable of rapid separation of CTCs, (3) Future direction on development of new technologies for CTC profiling. Current CTC researches have helped on identifying patients who may benefit from chemotherapy before treatment, patients who may benefit from continued chemotherapy, and leading to clinical development of CTC-guided chemotherapy strategies. We analyze the feasibility of clinical application of these current CTC research for the ultimate goal of increasing the survivability of cancer patient. The biomolecular assays of viable CTCs from cancer patient may elucidate the mechanism of metastasis and tumor initiating cells and also may have high impact on the development of personalized medicine to overcome the incurable diseases.

Preface.- Stem Cells and Prostate Development.- Isolation and Characterization of Prostate Stem Cells.- Prostate tumor initiating cells.- TIC Markers and methods of characterization.- Genetic Control of Self Renewal of the TIC.- Therapeutic targeting of the prostate TIC.- The prostate stem cell niche.- Tumor stroma control of the prostate TIC.- Targeting the prostate stem cell for chemoprevention.- Stem cell models for functional validation of prostate cancer genes.- Index.

e16091Background: Tumor initiating cells represent a minor cell subpopulation that is resistant to therapies and has cancer stem cell characteristics including self-renewal, multiple lineage differ...