Naira V Margaryan1,2,3, Elisabeth A Seftor1,2,3, Richard E B Seftor1,2,3, Mary J C Hendrix4,2,3. 1. Department of Biochemistry, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV 26506 USA. 2. Cancer Institute, West Virginia University, Morgantown, WV 26506 USA. 3. Department of Biology, Shepherd University, Shepherdstown, WV 25443 USA. 4. Department of Internal Medicine, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV 26506 USA.
Abstract
PURPOSE OF REVIEW: Cancer is a major public health problem worldwide. In aggressive cancers, which are heterogeneous in nature, there exists a paucity of targetable molecules that can be used to predict outcome and response to therapy in patients, especially those in the high risk category with a propensity to relapse following chemotherapy. This review addresses the challenges pertinent to treating aggressive cancer cells with inherent stem cell properties, with a special focus on triple-negative breast cancer (TNBC). RECENT FINDINGS: Plasticity underlies the cancer stem cell (CSC) phenotype in aggressive cancers like TNBC. Progenitors and CSCs implement similar signaling pathways to sustain growth, and the convergence of embryonic and tumorigenic signaling pathways has led to the discovery of novel oncofetal targets, rigorously regulated during normal development, but aberrantly reactivated in aggressive forms of cancer. SUMMARY: Translational studies have shown that Nodal, an embryonic morphogen, is reactivated in aggressive cancers, but not in normal tissues, and underlies tumor growth, invasion, metastasis and drug resistance. Front-line therapies do not inhibit Nodal, but when a combinatorial approach is used with an agent such as doxorubicin followed by anti-Nodal antibody therapy, significant decreases in cell growth and viability occur. These findings are of special interest in the development of new therapeutic interventions that target the stem cell properties of cancer cells to overcome drug resistance and metastasis.
PURPOSE OF REVIEW: Cancer is a major public health problem worldwide. In aggressive cancers, which are heterogeneous in nature, there exists a paucity of targetable molecules that can be used to predict outcome and response to therapy in patients, especially those in the high risk category with a propensity to relapse following chemotherapy. This review addresses the challenges pertinent to treating aggressive cancer cells with inherent stem cell properties, with a special focus on triple-negative breast cancer (TNBC). RECENT FINDINGS: Plasticity underlies the cancer stem cell (CSC) phenotype in aggressive cancers like TNBC. Progenitors and CSCs implement similar signaling pathways to sustain growth, and the convergence of embryonic and tumorigenic signaling pathways has led to the discovery of novel oncofetal targets, rigorously regulated during normal development, but aberrantly reactivated in aggressive forms of cancer. SUMMARY: Translational studies have shown that Nodal, an embryonic morphogen, is reactivated in aggressive cancers, but not in normal tissues, and underlies tumor growth, invasion, metastasis and drug resistance. Front-line therapies do not inhibit Nodal, but when a combinatorial approach is used with an agent such as doxorubicin followed by anti-Nodal antibody therapy, significant decreases in cell growth and viability occur. These findings are of special interest in the development of new therapeutic interventions that target the stem cell properties of cancer cells to overcome drug resistance and metastasis.
Entities:
Keywords:
Breast cancer; Cancer stem cells; Combinatorial therapy; Doxorubicin; Nodal; Predictive biomarker
Authors: Daisy W J van der Schaft; Femke Hillen; Patrick Pauwels; Dawn A Kirschmann; Karolien Castermans; Mirjam G A Oude Egbrink; Maxine G B Tran; Rafael Sciot; Esther Hauben; Pancras C W Hogendoorn; Olivier Delattre; Patrick H Maxwell; Mary J C Hendrix; Arjan W Griffioen Journal: Cancer Res Date: 2005-12-15 Impact factor: 12.701
Authors: Lynne-Marie Postovit; Elisabeth A Seftor; Richard E B Seftor; Mary J C Hendrix Journal: Expert Opin Ther Targets Date: 2007-04 Impact factor: 6.902
Authors: M Bittner; P Meltzer; Y Chen; Y Jiang; E Seftor; M Hendrix; M Radmacher; R Simon; Z Yakhini; A Ben-Dor; N Sampas; E Dougherty; E Wang; F Marincola; C Gooden; J Lueders; A Glatfelter; P Pollock; J Carpten; E Gillanders; D Leja; K Dietrich; C Beaudry; M Berens; D Alberts; V Sondak Journal: Nature Date: 2000-08-03 Impact factor: 49.962
Authors: Rosemarie C D'Angelo; Maria Ouzounova; April Davis; Daejin Choi; Stevie M Tchuenkam; Gwangil Kim; Tahra Luther; Ahmed A Quraishi; Yasin Senbabaoglu; Sarah J Conley; Shawn G Clouthier; Khaled A Hassan; Max S Wicha; Hasan Korkaya Journal: Mol Cancer Ther Date: 2015-02-11 Impact factor: 6.261
Authors: Luigi Strizzi; Lynne-Marie Postovit; Naira V Margaryan; Alina Lipavsky; Jules Gadiot; Christian Blank; Richard Eb Seftor; Elisabeth A Seftor; Mary Jc Hendrix Journal: Expert Rev Dermatol Date: 2009
Authors: Enza Lonardo; Patrick C Hermann; Maria-Theresa Mueller; Stephan Huber; Anamaria Balic; Irene Miranda-Lorenzo; Sladjana Zagorac; Sonia Alcala; Iker Rodriguez-Arabaolaza; Juan Carlos Ramirez; Raul Torres-Ruíz; Elena Garcia; Manuel Hidalgo; David Álvaro Cebrián; Rainer Heuchel; Matthias Löhr; Frank Berger; Peter Bartenstein; Alexandra Aicher; Christopher Heeschen Journal: Cell Stem Cell Date: 2011-11-04 Impact factor: 24.633
Authors: Gabriela Dontu; Kyle W Jackson; Erin McNicholas; Mari J Kawamura; Wissam M Abdallah; Max S Wicha Journal: Breast Cancer Res Date: 2004-08-16 Impact factor: 6.466
Authors: Naira V Margaryan; Hannah Hazard-Jenkins; Mohamad A Salkeni; Matthew B Smolkin; James A Coad; Sijin Wen; Elisabeth A Seftor; Richard E B Seftor; Mary J C Hendrix Journal: Cancers (Basel) Date: 2019-03-08 Impact factor: 6.639