Epithelial-mesenchymal transitions (EMTs) are a key requirement for cancer cells to metastasize and colonize in a new environment. Epithelial-mesenchymal plasticity is mediated by master transcription factors and is also subject to complex epigenetic regulation. This Review outlines our current understanding of the interactions between EMT-inducing transcription factors and epigenetic modulators during cancer progression and the therapeutic implications of exploiting this intricate regulatory process. During the course of malignant cancer progression, neoplastic cells undergo dynamic and reversible transitions between multiple phenotypic states, the extremes of which are defined by the expression of epithelial and mesenchymal phenotypes. This plasticity is enabled by underlying shifts in epigenetic regulation. A small cohort of pleiotropically acting transcription factors is widely recognized to effect these shifts by controlling the expression of a constituency of key target genes. These master regulators depend on complex epigenetic regulatory mechanisms, notably the induction of changes in the modifications of chromatin-associated histones, in order to achieve the widespread changes in gene expression observed during epithelial-mesenchymal transitions (EMTs). These associations indicate that an understanding of the functional interactions between such EMT-inducing transcription factors and the modulators of chromatin configuration will provide crucial insights into the fundamental mechanisms underlying cancer progression and may, in the longer term, generate new diagnostic and therapeutic modalities for treating high-grade malignancies.

The epigenetics of epithelial-mesenchymal plasticity in cancer

Cancer stem cells (CSCs), also known as tumor-initiating cells (TICs), are suggested to be responsible for drug resistance and cancer relapse due in part to their ability to self-renew themselves and differentiate into heterogeneous lineages of cancer cells. Thus, it is important to understand the characteristics and mechanisms by which CSCs display resistance to therapeutic agents. In this review, we highlight the key features and mechanisms that regulate CSC function in drug resistance as well as recent breakthroughs of therapeutic approaches for targeting CSCs. This promises new insights of CSCs in drug resistance and provides better therapeutic rationales to accompany novel anticancer therapeutics.

/pdf/cancer-stem-cells-cscs-in-drug-resistance-and-their-2kff3rft6m.pdf

Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment.

The use of biomarkers in diagnosis, therapy and prognosis has gained increasing interest over the last decades. In particular, the analysis of biomarkers in cancer patients within the pre- and post-therapeutic period is required to identify several types of cells, which carry a risk for a disease progression and subsequent post-therapeutic relapse. Cancer stem cells (CSCs) are a subpopulation of tumor cells that can drive tumor initiation and can cause relapses. At the time point of tumor initiation, CSCs originate from either differentiated cells or adult tissue resident stem cells. Due to their importance, several biomarkers that characterize CSCs have been identified and correlated to diagnosis, therapy and prognosis. However, CSCs have been shown to display a high plasticity, which changes their phenotypic and functional appearance. Such changes are induced by chemo- and radiotherapeutics as well as senescent tumor cells, which cause alterations in the tumor microenvironment. Induction of senescence causes tumor shrinkage by modulating an anti-tumorigenic environment in which tumor cells undergo growth arrest and immune cells are attracted. Besides these positive effects after therapy, senescence can also have negative effects displayed post-therapeutically. These unfavorable effects can directly promote cancer stemness by increasing CSC plasticity phenotypes, by activating stemness pathways in non-CSCs, as well as by promoting senescence escape and subsequent activation of stemness pathways. At the end, all these effects can lead to tumor relapse and metastasis. This review provides an overview of the most frequently used CSC markers and their implementation as biomarkers by focussing on deadliest solid (lung, stomach, liver, breast and colorectal cancers) and hematological (acute myeloid leukemia, chronic myeloid leukemia) cancers. Furthermore, it gives examples on how the CSC markers might be influenced by therapeutics, such as chemo- and radiotherapy, and the tumor microenvironment. It points out, that it is crucial to identify and monitor residual CSCs, senescent tumor cells, and the pro-tumorigenic senescence-associated secretory phenotype in a therapy follow-up using specific biomarkers. As a future perspective, a targeted immune-mediated strategy using chimeric antigen receptor based approaches for the removal of remaining chemotherapy-resistant cells as well as CSCs in a personalized therapeutic approach are discussed.

/pdf/cancer-stem-cells-origins-and-biomarkers-perspectives-for-3dc13vtybn.pdf

Cancer Stem Cells-Origins and Biomarkers: Perspectives for Targeted Personalized Therapies.

Pancreatic ductal adenocarcinoma (PDAC), generally known as pancreatic cancer (PC), ranks the fourth leading cause of cancer-related deaths in the western world. While the incidence of pancreatic cancer is displaying a rising tendency every year, the mortality rate has not decreased significantly because of late diagnosis, early metastasis, and limited reaction to chemotherapy or radiotherapy. Adjuvant chemotherapy after surgical resection is typically the preferred option to treat early pancreatic cancer. Although 5-fluorouracil/leucovorin with irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel can profoundly improve the prognosis of advanced pancreatic cancer, the development of chemoresistance still leads to poor clinical outcomes. Chemoresistance is multifactorial as a result of the interaction among pancreatic cancer cells, cancer stem cells, and the tumor microenvironment. Nevertheless, more pancreatic cancer patients will benefit from precision treatment and targeted drugs. Therefore, we outline new perspectives for enhancing the efficacy of gemcitabine after reviewing the related factors of gemcitabine metabolism, mechanism of action, and chemoresistance.

https://www.mdpi.com/1422-0067/20/18/4504/pdf

Chemoresistance in Pancreatic Cancer.

Myeloid-derived suppressor cells (MDSCs) are innate immune cells that acquire the capacity to suppress adaptive immune responses during cancer. It remains elusive how MDSCs differ from their normal myeloid counterparts, which limits our ability to specifically detect and therapeutically target MDSCs during cancer. Here, we sought to determine the molecular features of breast cancer-associated MDSCs using the widely studied mouse model based on the mouse mammary tumor virus (MMTV) promoter-driven expression of the polyomavirus middle T oncoprotein (MMTV-PyMT). To identify MDSCs in an unbiased manner, we used single-cell RNA sequencing to compare MDSC-containing splenic myeloid cells from breast tumor-bearing mice with wild-type controls. Our computational analysis of 14,646 single-cell transcriptomes revealed that MDSCs emerge through an aberrant neutrophil maturation trajectory in the spleen that confers them an immunosuppressive cell state. We establish the MDSC-specific gene signature and identify CD84 as a surface marker for improved detection and enrichment of MDSCs in breast cancers.

Defining the emergence of myeloid-derived suppressor cells in breast cancer using single-cell transcriptomics

The Hedgehog (Hh) pathway is a signaling cascade that plays a crucial role in many fundamental processes, including embryonic development and tissue homeostasis. Moreover, emerging evidence has suggested that aberrant activation of Hh is associated with neoplastic transformations, malignant tumors, and drug resistance of a multitude of cancers. At the molecular level, it has been shown that Hh signaling drives the progression of cancers by regulating cancer cell proliferation, malignancy, metastasis, and the expansion of cancer stem cells (CSCs). Thus, a comprehensive understanding of Hh signaling during tumorigenesis and development of chemoresistance is necessary in order to identify potential therapeutic strategies to target various human cancers and their relapse. In this review, we discuss the molecular basis of the Hh signaling pathway and its abnormal activation in several types of human cancers. We also highlight the clinical development of Hh signaling inhibitors for cancer therapy as well as CSC-targeted therapy.

https://www.mdpi.com/2073-4409/7/11/208/pdf

Hedgehog Signaling in Cancer: A Prospective Therapeutic Target for Eradicating Cancer Stem Cells.

https://www.exphem.org/article/S0301-472X(16)00063-1/pdf

Tetraspanins: Spanning from solid tumors to hematologic malignancies.

Metabolism and function of polyamines in cancer progression.

// Ita Novita Sari 1, * , Ying-Gui Yang 1, * , Lan Thi Hanh Phi 1 , Hyungjoo Kim 2 , Moo Jun Baek 3 , Dongjun Jeong 2 , Hyog Young Kwon 1 1 Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Republic of Korea 2 Soonchunhyang Medical Science Research Institute, College of Medicine, Soonchunhyang University, Republic of Korea 3 Department of Surgery, Department of Pathology, College of Medicine, Soonchunhyang University, Republic of Korea * These authors contributed equally to this work Correspondence to: Hyog Young Kwon, email: hykwon@sch.ac.kr Dongjun Jeong, email: juny1024@sch.ac.kr Keywords: IFITM1, colorectal cancer, prognosis, metastasis Received: June 06, 2016      Accepted: November 07, 2016      Published: November 12, 2016 ABSTRACT Interferon-induced transmembrane protein 1 (IFITM1) has been shown to be implicated in multiple cancers, yet little is known about biological significance of IFITM1 in colorectal cancer. Here, we show that IFITM1 is highly expressed in metastatic colorectal cancer cell lines as well as colorectal patient-derived tumor samples, and its expression is associated with a poor prognosis of the disease. Also, IFITM1 depletion resulted in a significant reduction in the mobility of cancer cell lines, whereas ectopic expression of IFITM1 promoted the migration of cancer cells. Epithelial-mesenchymal transition (EMT) signature was dysregulated by both loss and gain of function of IFITM1, which was partially reverted by Caveolin-1 (CAV1). Therefore, these results suggest that IFITM1 may be a prognostic marker and an attractive target to achieve better therapeutic outcomes in colorectal cancer.

https://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=download&path%5B%5D=13325&path%5B%5D=42296

Ita Novita Sari

Papers

Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment.

Hedgehog Signaling in Cancer: A Prospective Therapeutic Target for Eradicating Cancer Stem Cells.

Tetraspanins: Spanning from solid tumors to hematologic malignancies.

Metabolism and function of polyamines in cancer progression.

Interferon-induced transmembrane protein 1 (IFITM1) is required for the progression of colorectal cancer