Abstract 2023: Isolation of breast tumor initiating cells (TICs) by exogenous delivery of the OCT4 transcription factor

Abstract

Tumor initiating cells (TICs) are being extensively studied for their role in tumor etiology, maintenance and resistance to treatment. We describe a novel approach to generate TICs by transduction of human primary breast cell preparations with exogenous expression of the OCT4 transcription factor. The OCT4 transduced breast colonies (OTBCs) underwent an immortalization process, as reflected by loss of p16 and enhanced telomerase expression. OTBCs exhibited cancer stem cell antigens, such as CD44high/CD24low/‐. These cells generated subcutaneous tumors in nude mice with colonization capabilities with 1–50 cells, thereby exhibiting TIC properties. Histological analysis of these tumors revealed poorly differentiated breast carcinomas. RNAi‐mediated knock‐down of OCT4 and downstream embryonic targets of OCT4 resulted in suppression of the self‐renewal ability. OCT4 over‐expression in these clones was molecularly associated with Epithelial‐to‐Mesenchymal Transition (EMT) gene signatures and strongly correlated with the claudin‐low intrinsic subtype of breast cancer. Our experimental approach provides a novel model system to dissect genes that could be used to effectively target breast cancer self‐renewal and tumor initiation.

Enrichment and characterization of cancer stem cells from a human non-small cell lung cancer cell line

“…Previous findings have identified that Oct4 and Sox2 are important in the regene ration of many CSCs (20)(21)(22). RT-PCR and IFS assays were used to validate the expression of Oct4 and Sox2 in the A549 spheres.…”

Metformin is synthetically lethal with glucose withdrawal in cancer cells

“…reprogram adult somatic cells into iPSCs (i.e., OCT4, SOX2, KLF4 and c-MYC) to support their tumor initiation capacity. [62][63][64][65] For instance, endogenous expression of the transcription factor OCT4-a master gene playing a pivotal role in the self-renewal and pluripotency of stem cells-in normal breast tissues has been found to induce aberrant self-renewal and expansion of undifferentiated early stem/ progenitor population. 62,63 Similarly to its functioning during somatic reprogramming to stemness, OCT4 overexpression in normal breast tissue results in an activation of self-renewal TFs that is concomitant with the repression of tumor suppressor genes, thus allowing cells to immortalize and gain SC-like features.…”

Current challenges in the therapeutic use of induced pluripotent stem cells (iPSCs) in cancer therapy

“…Exogenous expression of Oct4 in human primary breast cells results in transformation of cells with overexpressed telomerase and down-regulated p16. Further injection of these transformed cells in nude mice generated breast carcinomas with metastatic potential [31]. In another recent study, co-expression of both Oct4/Nanog enhanced malignancy in lung adenocarcinoma and induces epithelial-mesenchymal transition (EMT).…”