The Ever-Evolving Concept of the Cancer Stem Cell in Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is the 4th most frequent cause of cancer-related death worldwide, primarily due to the inherent chemoresistant nature and metastatic capacity of this tumor. The latter is believed to be mainly due to the existence of a subpopulation of highly plastic "stem"-like cells within the tumor, known as cancer stem cells (CSCs), which have been shown to have unique metabolic, autophagic, invasive, and chemoresistance properties that allow them to continuously self-renew and escape chemo-therapeutic elimination. As such, current treatments for the majority of PDAC patients are not effective and do not significantly impact overall patient survival (<7 months) as they do not affect the pancreatic CSC (PaCSC) population. In this context, it is important to highlight the need to better understand the characteristics of the PaCSC population in order to develop new therapies to target these cells. In this review, we will provide the latest updates and knowledge on the inherent characteristics of PaCSCs, particularly their unique biological properties including chemoresistance, epithelial to mesenchymal transition, plasticity, metabolism and autophagy.

Keywords: EMT; autophagy; cancer stem cells; chemoresistance; hybrid cancer cell; metabolism; metastasis; pancreatic cancer; plasticity.

Figure 1

Pancreatic Ductal Adenocarcinoma (PDAC) tumor complexity, diagnosis and treatment. PDAC tumors include several cell types that interact with one another to maintain the tumor and facilitate PDAC progression. The tumor microenvironment plays a critical role in supporting tumor maintenance and expansion. The major cell types that belong to the PDAC tumor microenvironment are Tumor-associated macrophages (TAMs), Cancer-associated fibroblasts (CAFs), Pancreatic stellate cells (PSCs) and Mesenchymal stem cells (MSCs). Standard of care treatments only affect the tumor bulk, and diagnostic markers still lack sensitivity to adequately diagnose PDAC at early stages.

Figure 2

Models of the cancer stem cell concept to explain tumor heterogeneity. (a) Classical view shows the two pathways of Cancer Stem Cells (CSCs) differentiation: symmetrically (self-renewal) resulting in two CSCs and asymmetrically (differentiation) giving rise to a CSCs and a transient/hybrid cancer cell that gives rise to the more differentiated cells. These more differentiated cells divide rapidly and have less tumorigenic potential and plasticity compared to CSCs or transient/hybrid cancer cells. (b) Nowadays, this classical model has undergone some modifications. CSCs receive necessary signals from the tumor niche/tumor microenvironment (TME) modulating the path taken for their division. Due to the plasticity of the transient/hybrid daughter cells, they can also undergo reprogramming into a CSC via signals received from the tumor niche/TME. In addition, transient/hybrid cells can also give rise to differentiated bulk cancer cells.

Figure 3

Pancreatic CSCs features. Pancreatic CSCs (PaCSCs) include various CSC subpopulations with distinct characteristics. This figure shows some of the PaCSCs features, which may not be shared between all subpopulations. PaCSCs can express several markers for stemness, metastatic potential, immuno evasion and chemoresistance, as well as receptors for epithelial to mesenchymal transition (EMT) induction. Oxidative phosphorylation (OXPHOS) is a key feature of PaCSCs, as is enhanced autophagy and the accumulation of autofluorescent vesicles. Numerous stemness and chemoresistance signaling pathways may also be activated, strengthening CSC survival and PDAC progression, as well as relapse after treatment. JAK/STAT (Janus tyrosine Kinase/Signal Transducer and Activator of Transcription); PI3K (phosphatidylinositol 3-kinase); PGC-1 α (Peroxisome proliferator-activated receptor γ co-activator 1 α).

Figure 4

Redefining the roles of pancreatic cancer cells. (a) Inside the PDAC tumor we can find different types of tumor cells (TC), which have different states of differentiation and stemness: CSCs receive stimuli from the tumor niche that can influence the biology and overall status of the tumor as a whole and help CSCs maintain their stemness. In turn, CSCs can enter into an intermediate state of differentiation in which they maintain some of their stem capacity and express typical markers of differentiated TCs (hybrid/transient cancer cells). (b) Transient/hybrid cancer cells are able to survive under certain conditions and to regenerate tumor heterogeneity under therapeutic insult. For this reason, if combination therapies with anti-CSC/anti-tumor niche/anti-transient cell efficacy are used, it would be possible to eradicate the tumor in a more effective way. (c) Moreover, transient cancer cells are able to survive in the bloodstream and metastasize (e.g., to the liver) due to upregulation of CSC metastasis receptors such as CXCR4 and immune evasion receptors (PDL-1, CD47, DKK-1) and downregulation of death receptors (TRAILR and ULBP) and enter into a quiescent and immune evasion state.