The plasticity of pancreatic cancer stem cells: implications in therapeutic resistance

Abstract

The ever-growing perception of cancer stem cells (CSCs) as a plastic state rather than a hardwired defined entity has evolved our understanding of the functional and biological plasticity of these elusive components in malignancies. Pancreatic cancer (PC), based on its biological features and clinical evolution, is a prototypical example of a CSC-driven disease. Since the discovery of pancreatic CSCs (PCSCs) in 2007, evidence has unraveled their control over many facets of the natural history of PC, including primary tumor growth, metastatic progression, disease recurrence, and acquired drug resistance. Consequently, the current near-ubiquitous treatment regimens for PC using aggressive cytotoxic agents, aimed at ''tumor debulking'' rather than eradication of CSCs, have proven ineffective in providing clinically convincing improvements in patients with this dreadful disease. Herein, we review the key hallmarks as well as the intrinsic and extrinsic resistance mechanisms of CSCs that mediate treatment failure in PC and enlist the potential CSC-targeting 'natural agents' that are gaining popularity in recent years. A better understanding of the molecular and functional landscape of PCSC-intrinsic evasion of chemotherapeutic drugs offers a facile opportunity for treating PC, an intractable cancer with a grim prognosis and in dire need of effective therapeutic advances.

Keywords: Cancer stem cells; Drug resistance; Epithelial to mesenchymal transition; Oncogenic signaling; Pancreatic cancer.

Fig. 1

Key signaling pathways regulating CSC state in pancreatic cancer. Amongst an array of signaling pathways aberrantly activated in PCSCs, Notch, Wnt, and Hedgehog pathways are crucial for the maintenance of self-renewal, tumor development, invasion, metastasis, and therapy-resistance. In the canonical Hedgehog pathway, binding of the exogenous Hh ligand to its cognate receptor Ptch removes the inhibitory influence of Ptch on Smo, thereby activating Smo and the downstream Gli proteins, which upon nuclear translocation induces target (stemness) gene expression. The canonical Wnt signaling pathway is activated upon binding of the Wnt ligand to the seven-transmembrane receptor Frizzled and the single-membrane-spanning LRP5/6. Frizzled then recruits the intracellular protein Dishevelled leading to the decomposition of the multiprotein β-catenin destruction complex that includes serine/threonine kinases GSK3 and CK1 and tumor suppressors Axin and APC. This results in the accumulation of the active unphosphorylated β-catenin followed by its translocation to the nucleus where it regulates the target gene transcription. The Notch pathway is induced when a delta-like or Jagged ligand binds to the extracellular domain of the Notch transmembrane receptor. This binding causes the proteolytic cleavage of an intracellular fragment NICD which, upon release, localizes to the nucleus and functions to regulate transcription of Notch target genes by interacting with CSL and coregulators. CSL CBF1/Suppressor of Hairless/LAG-1, NICD Notch intracellular domain, LRP5/6 Low-density lipoprotein receptor related protein 5/6, APC Adenomatous polyposis coli, TCF/LEF T-cell factor/lymphoid enhancer factor, CK1 Casein kinase 1, SUFU suppressor of fused protein, and MAM Mastermind

Fig. 2

CSC-mediated mechanisms underscoring therapeutic resistance in pancreatic cancer. Multiple intrinsic and extrinsic mechanisms induce the chemoresistant phenotype in PCSCs. When a tumor is exposed to systemic chemotherapy and/or loco-regional radiation therapy, the majority of the bulk tumor cells get eradicated but not the CSCs. In due course, a CSC niche is created that favors the stemness potential and activity in CSCs. The oncogenic insults also favor the bidirectional conversion between CSCs and non-CSCs; tumor cells undergo genome reprogramming and dedifferentiate to a progenitor/stem cell state and create a new pool of CSCs. Eventually, these therapy-resistant CSCs expand and repopulate the tumor and generate additional therapy-resistant CSC progeny. This tumor plasticity leads to tumor relapse and recurrence. During treatment or post-therapy, PCSCs display several features such as improved DNA repair capacity, a higher degree of drug efflux activity, increased metabolic reprogramming, quiescence, EMT, enhanced autophagy, epigenetic modifications, tumor microenvironmental interactions, and dysregulated developmental pathways that all enable them to stay resilient within a tumor, evade anti-proliferative therapies, and recur in post-therapy cancer patients

Fig. 3

The primary tumor microenvironment in pancreatic cancer—emphasis on pancreatic stellate cells. The pancreatic TME is characterized by dense desmoplastic stroma that is majorly occupied by PSCs (nearly 50%). Upon activation by inflammatory signals such as TGF-β1, PSCs present myofibroblast-like phenotype, recruit immunosuppressive cells (MDSCs, TAMs, and Treg cells), and secrete ECM components (collagen, laminin, fibronectin, and HA), inflammatory cytokines (IL-6 and tumor necrosis factor (TNF)-ɑ), pro-angiogenic factors (VEGF), matrix metalloproteinases (MMP-2,9), growth factors (platelet-derived growth factor (PDGF)), and non-essential amino acids (alanine, aspartate). Two major subtypes of CAF have been identified within the tumor stroma, iCAFs and myCAFs. This complexity of the pancreatic tumor TME fosters rapid growth, enhances invasive and metastatic potentials, confers a survival advantage in hypoxic and low-nutrient conditions, and bestows therapy-resistance capabilities in PCSCs and PC cells. iCAFs inflammatory cancer-associated fibroblasts, myCAFs myofibroblastic cancer-associated fibroblasts, Treg cell regulatory T cell, MDSC myeloid-derived suppressor cells, and AA amino acids