Pancreatic cancer stem cells: A state or an entity?

Abstract

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, has a median overall survival of 6-12 months and a 5-year survival of less than 7%. While PDAC currently represents the 4th most frequent cause of death due to cancer worldwide, it is expected to become the second leading cause of cancer-related death by 2030. These alarming statistics are primarily due to both the inherent chemoresistant and metastatic nature of this tumor, and the existence of a subpopulation of highly plastic "stem"-like cells within the tumor, known as cancer stem cells (CSCs). Since their discovery in PDAC in 2007, we have come to realize that pancreatic CSCs have unique metabolic, autophagic, invasive, and chemoresistance properties that allow them to continuously self-renew and escape chemo-therapeutic elimination. More importantly, the concept of the CSC as a fixed entity within the tumor has also evolved, and current data suggest that CSCs are states rather than defined entities. Consequently, current treatments for the majority of PDAC patients are not effective, and do not significantly impact overall patient survival, as they do not adequately target the plastic CSC sub-population nor the transient/hybrid cells that can replenish the CSC pool. Thus, it is necessary that we improve our understanding of the characteristics and signals that maintain and drive the pancreatic CSC population in order to develop new therapies to target these cells. Herein, we will provide the latest updates and knowledge on the inherent characteristics of pancreatic CSCs and the CSC niche, specifically the cross-talk that exists between CSCs and niche resident cells. Lastly, we will address the question of whether a CSC is a state or an entity and discuss how the answer to this question can impact treatment approaches.

Targeting SRC Kinase Signaling in Pancreatic Cancer Stem Cells

“…Thus, from a clinical perspective, the effective targeting and elimination of CSCs should lead to tumor elimination. Unfortunately, since their discovery in acute myeloid leukemia in 1994 [ 4 ], the development of anti-CSC-specific therapies has proven difficult due to the genetic and nongenetic factors underlying the inherent CSC state and the plasticity that exists between CSCs and non-CSCs [ 5 ]. As a consequence, to date, only a handful of anti-CSC-specific therapies exist, but many promising therapies are in clinical trials (reviewed in Yang et al [ 6 ]).…”

Cancer stem cells (CSCs) in cancer progression and therapy

“…Adenosine has been identified as a potent proinvasive factor (Siriwon et al, 2018), and it is a strong stimulator of Treg immunosuppressive activity (Ghalamfarsa et al, 2018) and a suppressor of CTLs (Y. . Cross-talking between CSCs with other cells within TME has been shown in proliferative rates and are not responsible for long-term tumor growth (Batlle & Clevers, 2017;Hermann & Sainz, 2018). There is evidence that residual tumors are frequently enriched with CSCs, so the cells are essentially responsible for tumor rebound after therapy (Cazet et al, 2018).…”

Truncated O‐glycans promote epithelial‐to‐mesenchymal transition and stemness properties of pancreatic cancer cells

“…It is well known that PDAC is composed of both undifferentiated or poorly differentiated cancer stem cells and more differentiated malignant cells that are derived from cancer stem cells. 20 Since we is depicted in Figure 3A. Interestingly, a significant increase in the percentage of side cell population (SP) was observed in T3M4 SC cells (1.57% ± 0.22) when compared with WT cells (0.54% ± 0.05) (P = 0.0163).…”

“…It is well known that PDAC is composed of both undifferentiated or poorly differentiated cancer stem cells and more differentiated malignant cells that are derived from cancer stem cells . Since we found that cancer‐specific truncation of O‐glycans enhanced the oncogenic features through the induction of EMT, we sought to explore the possibility of truncated O‐glycans induced stem cell side populations in PDAC cells as EMT is closely associated with cellular plasticity .…”