EGFR Inhibition Abrogates Leiomyosarcoma Cell Chemoresistance through Inactivation of Survival Pathways and Impairment of CSC Potential

Abstract

BackgroundTumor cells with stem-like phenotype and properties, known as cancer stem cells (CSC), have been identified in most solid tumors and are presumed to be responsible for driving tumor initiation, chemoresistance, relapse, or metastasis. A subpopulation of cells with increased stem-like potential has also been identified within sarcomas. These cells are endowed with increased tumorigenic potential, chemoresistance, expression of embryonic markers, and side population(SP) phenotype. Leiomyosarcomas (LMS) are soft tissue sarcomas presumably arising from undifferentiated cells of mesenchymal origin, the Mesenchymal Stem Cells (MSC). Frequent recurrence of LMS and chemoresistance of relapsed patients may likely result from the failure to target CSC. Therefore, therapeutic cues coming from the cancer stem cell (CSC) field may drastically improve patient outcome.Methodology/Principal FindingsWe expanded LMS stem-like cells from patient samples in vitro and examined the possibility to counteract LMS malignancy through a stem-like cell effective approach. LMS stem-like cells were in vitro expanded both as “tumor spheres” and as “monolayers” in Mesenchymal Stem Cell (MSC) conditions. LMS stem-like cells displayed MSC phenotype, higher SP fraction, and increased drug-extrusion, extended proliferation potential, self-renewal, and multiple differentiation ability. They were chemoresistant, highly tumorigenic, and faithfully reproduced the patient tumor in mice. Such cells displayed activation of EGFR/AKT/MAPK pathways, suggesting a possibility in overcoming their chemoresistance through EGFR blockade. IRESSA plus Vincristine treatment determined pathway inactivation, impairment of SP phenotype, high cytotoxicity in vitro and strong antitumor activity in stem-like cell-generated patient-like xenografts, targeting both stem-like and differentiated cells.Conclusions/SignificanceEGFR blockade combined with vincristine determines stem-like cell effective antitumor activity in vitro and in vivo against LMS, thus providing a potential therapy for LMS patients.

E1B and E4 oncoproteins of adenovirus antagonize the effect of apoptosis inducing factor

“…Because the pathways governing growth, survival and death in tumor cells often differ from those in benign cells (Hsieh et al, 2012; Sette et al, 2012; Zeng et al, 2012), we evaluated additional cell lines for their susceptibility to nuclear fragmentation by the double-mutant virus. In both cervical cancer-derived HeLa cells and prostate cancer-derived PC3 cells, the frequency of cells with fragmented nuclei after infection with wild-type and single-mutant adenoviruses was the same as mock-infected cells (Fig.…”

Clinical Outcomes and Prognostic Markers in Uterine Leiomyosarcoma: A Population-Based Cohort

“…4,22 Although EGFR expression was not prognostic for recurrence or survival in our cohort, the ongoing study of tyrosine kinase inhibitor therapy targeting EGFR-associated pathway mutations is supported by recent encouraging findings of preclinical and clinical activity in leiomyosarcoma. 23,24 It remains unknown whether the administration of adjuvant chemotherapy can prolong RFS or OS for apparent uterine-confined disease and is the subject of an ongoing phase 3 randomized international cooperative group trial. Hensley et al 25 conducted a phase 2 trial of adjuvant gemcitabine plus docetaxel followed by doxorubicin in 47 patients with apparently uterine-confined leiomyosarcoma.…”

Targeting protein kinases to reverse multidrug resistance in sarcoma

“…Thirty-two types of NRTKs have been identified and divided into 10 subfamilies, including SRC, ABL, JAK, and Focal adhesion kinase (FAK). Aberrant expression of certain tyrosine kinases and/or constitutive activation of downstream pathways may be responsible for the progression of sarcoma, including tumor cell survival, apoptosis, neovascularization, and invasion, particularly in MDR 9 . Accumulating evidence reveals that tyrosine kinases are highly expressed in sarcoma, such as overexpression of JAK1 in Ewing sarcoma, EGFR and PDGFRA in synovial sarcoma, and FGFR in osteosarcoma and rhabdomyosarcoma 10 .…”

“…In a study that demonstrated highly activated EGFR in leiomyosarcoma, the use of an EGFR inhibitor showed a potent ability to overcome MDR 9 . The group investigated the effect of EGFR inhibitor gefitinib on leiomyosarcoma stem-like cells.…”