PTEN Tumor-Suppressor: The Dam of Stemness in Cancer

PTEN is one of the most frequently inactivated tumor suppressor genes in cancer. Loss or variation in PTEN gene/protein levels is commonly observed in a broad spectrum of human cancers, while germline PTEN mutations cause inherited syndromes that lead to increased risk of tumors. PTEN restrains tumorigenesis through different mechanisms ranging from phosphatase-dependent and independent activities, subcellular localization and protein interaction, modulating a broad array of cellular functions including growth, proliferation, survival, DNA repair, and cell motility. The main target of PTEN phosphatase activity is one of the most significant cell growth and pro-survival signaling pathway in cancer: PI3K/AKT/mTOR. Several shreds of evidence shed light on the critical role of PTEN in normal and cancer stem cells (CSCs) homeostasis, with its loss fostering the CSC compartment in both solid and hematologic malignancies. CSCs are responsible for tumor propagation, metastatic spread, resistance to therapy, and relapse. Thus, understanding how alterations of PTEN levels affect CSC hallmarks could be crucial for the development of successful therapeutic approaches. Here, we discuss the most significant findings on PTEN-mediated control of CSC state. We aim to unravel the role of PTEN in the regulation of key mechanisms specific for CSCs, such as self-renewal, quiescence/cell cycle, Epithelial-to-Mesenchymal-Transition (EMT), with a particular focus on PTEN-based therapy resistance mechanisms and their exploitation for novel therapeutic approaches in cancer treatment.

Download Full-text

The Role of Calcium Signaling in Regulation of Epithelial-Mesenchymal Transition

Cells Tissues Organs ◽

10.1159/000512277 ◽

2020 ◽

pp. 1-23

Author(s):

Divya Adiga ◽

Raghu Radhakrishnan ◽

Sanjiban Chakrabarty ◽

Prashant Kumar ◽

Shama Prasada Kabekkodu

Keyword(s):

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Critical Role ◽

Cancer Therapeutics ◽

Growth And Survival ◽

Mesenchymal Transition ◽

Microenvironmental Factors ◽

Favorable Clinical Outcome

Despite substantial advances in the field of cancer therapeutics, metastasis is a significant challenge for a favorable clinical outcome. Epithelial to mesenchymal transition (EMT) is a process of acquiring increased motility, invasiveness, and therapeutic resistance by cancer cells for their sustained growth and survival. A plethora of intrinsic mechanisms and extrinsic microenvironmental factors drive the process of cancer metastasis. Calcium (Ca2+) signaling plays a critical role in dictating the adaptive metastatic cell behavior comprising of cell migration, invasion, angiogenesis, and intravasation. By modulating EMT, Ca2+ signaling can regulate the complexity and dynamics of events leading to metastasis. This review summarizes the role of Ca2+ signal remodeling in the regulation of EMT and metastasis in cancer.

Download Full-text

Extracellular HSP90α-LRP1 Signaling Promote Pancreatic Cancer Metastasis and Chemoresistance Via Regulating Epithelial-To-Mesenchymal Transition

10.21203/rs.3.rs-1088653/v1 ◽

2021 ◽

Author(s):

Nina Xue ◽

Tingting Du ◽

Fangfang Lai ◽

Jing Jin ◽

Ming Ji ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Critical Role ◽

Density Lipoprotein ◽

Underlying Mechanism ◽

Migration And Invasion ◽

Mesenchymal Transition

Abstract Extracellular heat shock protein 90α (HSP90α) has been reported to promote cancer cell invasion and migration. However, whether pancreatic cancer (PC) cells expressed membrane-bound or secreted HSP90α and its underlying mechanism for PC progression were still unclear. Our study pointed out that highly invasive Capan2 cells has a higher level of secreted HSP90α, rather than membrane HSP90α, compared with those of less invasive PL45 cells. The conditioned medium of Capan2 cells or recombinant HSP90α protein was able to stimulate the migration and invasion of PL45 or capan2 cells, which could be prevented by a neutralizing anti-HSP90α antibody. Furthermore, secreted HSP90α promoted elements of epithelial-mesenchymal transition (EMT) in PL45 cells, including increases in vimentin and snail expressions, decreases in E-cadherin expression and changes in cell shape towards a mesenchymal phenotype, but these phenomena were reversed by anti-HSP90α antibody in Capan2 cells. In addition, high levels of low-density lipoprotein receptor-related protein 1 (LRP1) mRNA were associated with worsened patient survival in pancreatic adenocarcinoma. LRP1 as a receptor of eHSP90α for its stimulatory role of PC cells EMT and metastasis by activating AKT signaling. Down-regulation of LRP1 could promote chemosensitivity to gemcitabine and doxorubicin, but not to topotecan and paclitaxel in Capan2 cells. Therefore, our study reveals a critical role of secreted HSP90α on EMT events and suggests blocking secreted HSP90α underlies an aspect of metastasis and chemoresistance.

Download Full-text

The Critical Role of TAK1 in Accentuated Epithelial to Mesenchymal Transition in Obliterative Bronchiolitis after Lung Transplantation

American Journal Of Pathology ◽

10.1016/j.ajpath.2012.02.022 ◽

2012 ◽

Vol 180 (6) ◽

pp. 2293-2308 ◽

Cited By ~ 17

Author(s):

Aaron Gardner ◽

Andrew J. Fisher ◽

Christine Richter ◽

Gail E. Johnson ◽

Elizabeth J. Moisey ◽

...

Keyword(s):

Lung Transplantation ◽

Epithelial To Mesenchymal Transition ◽

Critical Role ◽

Obliterative Bronchiolitis ◽

Mesenchymal Transition

Download Full-text

The Role of Cancer-Associated Fibroblasts in Cancer Invasion and Metastasis

Cancers ◽

10.3390/cancers13184720 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4720

Author(s):

Paris Jabeen Asif ◽

Ciro Longobardi ◽

Michael Hahne ◽

Jan Paul Medema

Keyword(s):

Cancer Progression ◽

Epithelial To Mesenchymal Transition ◽

Therapy Resistance ◽

Cancer Invasion ◽

Cancer Associated Fibroblasts ◽

Targeted Therapeutics ◽

Invasion And Metastasis ◽

Mesenchymal Transition ◽

Future Studies

Cancer-associated fibroblasts (CAFs) play a key role in cancer progression by contributing to extracellular matrix (ECM) deposition and remodeling, extensive crosstalk with cancer cells, epithelial-to-mesenchymal transition (EMT), invasion, metastasis, and therapy resistance. As metastasis is a main reason for cancer-related deaths, it is crucial to understand the role of CAFs in this process. Colorectal cancer (CRC) is a heterogeneous disease and lethality is especially common in a subtype of CRC with high stromal infiltration. A key component of stroma is cancer-associated fibroblasts (CAFs). To provide new perspectives for research on CAFs and CAF-targeted therapeutics, especially in CRC, we discuss the mechanisms, crosstalk, and functions involved in CAF-mediated cancer invasion, metastasis, and protection. This summary can serve as a framework for future studies elucidating these roles of CAFs.

Download Full-text

Lineage Plasticity in Cancer: The Tale of a Skin-walker

10.20944/preprints202105.0779.v1 ◽

2021 ◽

Author(s):

Archana P. Thankamony ◽

Ayalur Raghu Subbalakshmi ◽

Mohit Kumar Jolly ◽

Radhika Nair

Keyword(s):

Tumor Progression ◽

Tissue Repair ◽

Epithelial Mesenchymal Transition ◽

Therapy Resistance ◽

Therapeutic Resistance ◽

Therapeutic Approaches ◽

Mesenchymal Transition ◽

Lineage Switch ◽

Lymphoid Lineage

Lineage plasticity, the switching of cells from one lineage to another has been recognized to be a cardinal property essential for embryonic development, tissue repair and homeostasis. However, such a highly regulated process goes awry when cancer cells exploit this inherent ability to their advantage, resulting in tumorigenesis, relapse, metastasis and therapy resistance. In this review, we summarize our current understanding on the role of lineage plasticity in tumor progression and therapeutic resistance in multiple cancers. Lineage plasticity can be triggered by treatment itself and is reported across various solid as well as liquid tumors. Here we focus on the importance of lineage switching in tumor progression and therapeutic resistance of solid tumors such as the prostate, lung, hepatocellular and colorectal carcinoma and the myeloid and lymphoid lineage switch observed in leukemias. Besides this, we also discuss the role of Epithelial-Mesenchymal Transition (EMT) in facilitating the lineage switch in biphasic cancers such as aggressive carcinosarcomas. We also discuss the mechanisms involved, current therapeutic approaches and challenges that lie ahead in taming the scourge of lineage plasticity in cancer.

Download Full-text

Epithelial-to-Mesenchymal Transition in the Light of Plasticity and Hybrid E/M States

Journal of Clinical Medicine ◽

10.3390/jcm10112403 ◽

2021 ◽

Vol 10 (11) ◽

pp. 2403

Author(s):

Laura Bornes ◽

Guillaume Belthier ◽

Jacco van Rheenen

Keyword(s):

Wound Healing ◽

Cell Adhesion ◽

Basement Membrane ◽

Cell Polarity ◽

Cancer Progression ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Therapy Resistance ◽

Mesenchymal Transition

Epithelial-to-mesenchymal transition (EMT) is a cellular program which leads to cells losing epithelial features, including cell polarity, cell–cell adhesion and attachment to the basement membrane, while gaining mesenchymal characteristics, such as invasive properties and stemness. This program is involved in embryogenesis, wound healing and cancer progression. Over the years, the role of EMT in cancer progression has been heavily debated, and the requirement of this process in metastasis even has been disputed. In this review, we discuss previous discrepancies in the light of recent findings on EMT, plasticity and hybrid E/M states. Moreover, we highlight various tumor microenvironmental cues and cell intrinsic signaling pathways that induce and sustain EMT programs, plasticity and hybrid E/M states. Lastly, we discuss how recent findings on plasticity, especially on those that enable cells to switch between hybrid E/M states, have changed our understanding on the role of EMT in cancer metastasis, stemness and therapy resistance.

Download Full-text

Exosome-Mediated Signaling in Epithelial to Mesenchymal Transition and Tumor Progression

Journal of Clinical Medicine ◽

10.3390/jcm8010026 ◽

2018 ◽

Vol 8 (1) ◽

pp. 26 ◽

Cited By ~ 23

Author(s):

Alice Conigliaro ◽

Carla Cicchini

Keyword(s):

Tumor Progression ◽

Intercellular Communication ◽

Epithelial To Mesenchymal Transition ◽

Current Knowledge ◽

Cell Communication ◽

Therapeutic Approaches ◽

Mesenchymal Transition ◽

Rna Molecules ◽

Dna And Rna

Growing evidence points to exosomes as key mediators of cell–cell communication, by transferring their specific cargo (e.g., proteins, lipids, DNA and RNA molecules) from producing to receiving cells. In cancer, the regulation of the exosome-mediated intercellular communication may be reshaped, inducing relevant changes in gene expression of recipient cells in addition to microenvironment alterations. Notably, exosomes may deliver signals able to induce the transdifferentiation process known as Epithelial-to-Mesenchymal Transition (EMT). In this review, we summarize recent findings on the role of exosomes in tumor progression and EMT, highlighting current knowledge on exosome-mediated intercellular communication in tumor-niche establishment, migration, invasion, and metastasis processes. This body of evidence suggests the relevance of taking into account exosome-mediated signaling and its multifaceted aspects to develop innovative anti-tumoral therapeutic approaches.

Download Full-text

Lineage Plasticity in Cancer: The Tale of a Skin-Walker

Cancers ◽

10.3390/cancers13143602 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3602

Author(s):

Archana P. Thankamony ◽

Ayalur Raghu Subbalakshmi ◽

Mohit Kumar Jolly ◽

Radhika Nair

Keyword(s):

Tumor Progression ◽

Tissue Repair ◽

Epithelial Mesenchymal Transition ◽

Therapy Resistance ◽

Therapeutic Resistance ◽

Therapeutic Approaches ◽

Mesenchymal Transition ◽

Lineage Switch ◽

Lymphoid Lineage

Lineage plasticity, the switching of cells from one lineage to another, has been recognized as a cardinal property essential for embryonic development, tissue repair and homeostasis. However, such a highly regulated process goes awry when cancer cells exploit this inherent ability to their advantage, resulting in tumorigenesis, relapse, metastasis and therapy resistance. In this review, we summarize our current understanding on the role of lineage plasticity in tumor progression and therapeutic resistance in multiple cancers. Lineage plasticity can be triggered by treatment itself and is reported across various solid as well as liquid tumors. Here, we focus on the importance of lineage switching in tumor progression and therapeutic resistance of solid tumors such as the prostate, lung, hepatocellular and colorectal carcinoma and the myeloid and lymphoid lineage switch observed in leukemias. Besides this, we also discuss the role of epithelial-mesenchymal transition (EMT) in facilitating the lineage switch in biphasic cancers such as aggressive carcinosarcomas. We also discuss the mechanisms involved, current therapeutic approaches and challenges that lie ahead in taming the scourge of lineage plasticity in cancer.

Download Full-text

Src family kinases, adaptor proteins and the actin cytoskeleton in epithelial-to-mesenchymal transition

Cell Communication and Signaling ◽

10.1186/s12964-021-00750-x ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Maria A. Ortiz ◽

Tatiana Mikhailova ◽

Xiang Li ◽

Baylee A. Porter ◽

Alaji Bah ◽

...

Keyword(s):

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Human Cancer ◽

Critical Role ◽

Adaptor Proteins ◽

Src Family Kinases ◽

Invasion And Metastasis ◽

Mesenchymal Transition ◽

Epithelial Homeostasis

AbstractOver a century of scientific inquiry since the discovery of v-SRC but still no final judgement on SRC function. However, a significant body of work has defined Src family kinases as key players in tumor progression, invasion and metastasis in human cancer. With the ever-growing evidence supporting the role of epithelial-mesenchymal transition (EMT) in invasion and metastasis, so does our understanding of the role SFKs play in mediating these processes. Here we describe some key mechanisms through which Src family kinases play critical role in epithelial homeostasis and how their function is essential for the propagation of invasive signals.

Download Full-text

Active RAC1 Promotes Tumorigenic Phenotypes and Therapy Resistance in Solid Tumors

Cancers ◽

10.3390/cancers12061541 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1541

Author(s):

Pradip De ◽

Brett James Rozeboom ◽

Jennifer Carlson Aske ◽

Nandini Dey

Keyword(s):

Botulinum Toxin ◽

Solid Tumors ◽

Epithelial To Mesenchymal Transition ◽

Critical Role ◽

Copy Number Gain ◽

Therapy Resistance ◽

Cancer Therapies ◽

Mesenchymal Transition ◽

Therapeutic Modalities ◽

Development Of Resistance

Acting as molecular switches, all three members of the Guanosine triphosphate (GTP)-ase-family, Ras-related C3 botulinum toxin substrate (RAC), Rho, and Cdc42 contribute to various processes of oncogenic transformations in several solid tumors. We have reviewed the distribution of patterns regarding the frequency of Ras-related C3 botulinum toxin substrate 1 (RAC1)-alteration(s) and their modes of actions in various cancers. The RAC1 hyperactivation/copy-number gain is one of the frequently observed features in various solid tumors. We argued that RAC1 plays a critical role in the progression of tumors and the development of resistance to various therapeutic modalities applied in the clinic. With this perspective, here we interrogated multiple functions of RAC1 in solid tumors pertaining to the progression of tumors and the development of resistance with a special emphasis on different tumor cell phenotypes, including the inhibition of apoptosis and increase in the proliferation, epithelial-to-mesenchymal transition (EMT), stemness, pro-angiogenic, and metastatic phenotypes. Our review focuses on the role of RAC1 in adult solid-tumors and summarizes the contextual mechanisms of RAC1 involvement in the development of resistance to cancer therapies.

Download Full-text