Epithelial plasticity and cancer stem cells: Major mechanisms of cancer pathogenesis and therapy resistance

Abstract

Epithelial-mesenchymal transition (EMT) has been linked with aggressive tumor biology and therapy resistance. It plays central role not only in the generation of cancer stem cells (CSCs) but also direct them across the multiple organ systems to promote tumor recurrence and metastasis. CSCs are reported to express stem cell genes as well as specific cell surface markers and allow aberrant differentiation of progenies. It facilitates cancer cells to leave primary tumor, acquire migratory characteristics, grow into new environment and develop radio-chemo-resistance. Based on the current information, present review discusses and summarizes the recent advancements on the molecular mechanisms that derive epithelial plasticity and its major role in generating a subset of tumor cells with stemness properties and pathophysiological spread of tumor. This paper further highlights the critical need to examine the regulation of EMT and CSC pathways in identifying the novel probable therapeutic targets. These improved therapeutic strategies based on the co-administration of inhibitors of EMT, CSCs as well as differentiated tumor cells may provide improved anti-neoplastic response with no tumor relapse.

Inhibition of tumor growth and angiogenesis of tamoxifen‑resistant breast cancer cells by ruxolitinib, a selective JAK2 inhibitor

“…We and other groups have shown that EMT contributes to the enhanced migration ability of TAM-resistant breast cancer cells, which may be required for higher rates of metastasis (7)(8)(9). During EMT progression, morphological changes to highly motile mesenchymal cancer cells are associated with several molecular characteristics, including increased levels of N-cadherin and vimentin, reduced levels of E-cadherin and claudins, and the release of matrix remodeling enzymes such as matrix metalloproteinases (52). Changes in the expression patterns of these proteins have been shown to result from induction of EMT-activating transcription factors, such as the snail family of zinc finger transcription factors, basic helix-loop-helix factors, and twist (53).…”

“…In fact, JAK-STAT has been reported to be constitutively active in a triple-negative breast cancer (TNBC) cell line, MDA-MB-cells, and TNBC tumor tissues (12,(48)(49)(50), and an oral JAK inhibitor suppresses tumor growth and metastasis of TNBC cells in vitro and in vivo (51). In a terminated clinical study, single administration of ruxolitinib showed no objective responses in a treatment-refractory TNBC patient population (52). The authors indicated that the discrepancy between clinical outcomes and on-target activity may be due to intratumoral heterogeneity within individual TNBC biopsies (50).…”

Pin2 telomeric repeat factor 1-interacting telomerase inhibitor 1 (PinX1) inhibits nasopharyngeal cancer cell stemness: implication for cancer progression and therapeutic targeting

“…Over the years, increasing studies have focused on understanding the biological properties and mechanisms of CSC formation to develop novel strategies to identify these stem-like cancer cells and to target them specifically [22][23][24]. EMT is considered an important process that leads to tumor invasion and distant metastasis, and it has become an important biological characteristic of CSCs that confers new biological behaviors such as chemotherapy resistance, anti-radiation properties, recurrence, and distant metastasis [25]. Guen et al [26] demonstrated that EMT programs promote basal mammary stem cell and tumor-initiating cell stemness by inducing primary ciliogenesis and Hedgehog signaling.…”

DUOX2-mediated production of reactive oxygen species induces epithelial mesenchymal transition in 5-fluorouracil resistant human colon cancer cells

“…Although 5-FU-based chemotherapies benefit colon cancer patients, a large fraction of them relapse [28] , [29] . Chemo-resistance and metastasis remain a major problem in cancer treatment [30] , [31] . EMT has recently been identified as a critical player in 5-FU resistance and metastasis [32] , [33] .…”