Evolving Treatment Paradigms for Pancreatic Cancer

Abstract

<b><i>Background:</i></b> Pancreatic adenocarcinoma is an extremely aggressive tumor which is supposed to become the second deadliest malignancy in 2030. For a long time the possibilities to treat this complex disease were very limited. <b><i>Summary:</i></b> In the last years the development of new chemotherapeutic regimens has led to a better outcome in the ad­juvant, neoadjuvant, and palliative setting. Furthermore, progress in sequencing technologies has enabled a detailed investigation of the genetic alterations, mutational burden, expression pattern, and stroma composition in pancreatic cancer and led to the identification of subtypes of this disease. <b><i>Messages:</i></b> This analysis will increase our understanding of tumor heterogeneity and hopefully translate into new potential targets, biomarkers, and the development of individual therapeutic approaches in the future.

Targeting the Stroma in the Management of Pancreatic Cancer

“…Another recent investigation also established a stromal classification with two subtypes ECM-rich and immunerich, where the ECM-rich subtype was associated with a shorter survival compared to immune-rich tumours (15). Similar to this classification, digital deconvolution of transcriptomic data identified two distinct stromal-specific gene expression signatures: normal and activated, where normal stroma was dominated by markers for pancreatic stellate cells (PSCs), whereas activated stroma was characterized by inflammatory signatures associated with a significantly worse prognosis (16). Consequently, based on a better molecular characterization of PC that includes the stroma, targeting the appropriate stromal components may lead to a better outcome and represent a promising approach for precision medicine in PC treatment.…”

“…Along with HA, extracellular proteins, including connective tissue growth factor (CTGF) and secreted protein acidic and rich in cysteine (SPARC) are also essential for maintaining physiologic homeostasis and modulate multiple biologic processes, such as wound repair, tissue remodeling, angiogenesis, matrix cell adhesion, cell differentiation, proliferation, and migration (9,41). The functions of these molecules might be in part mediated by interaction with PSCs/CAFs and several growth factors, like TGF-b and fibroblast growth factor (FGF) (16). Although the role of ECM components in carcinogenesis remains controversial in PC, they are highly expressed in various types of cancer (42).…”

“…PC is known to exhibit a low mutation burden and lack of significant neoantigens, leading to the dysfunction of immune effector cells, such as T cells and natural killer cells (58,59). CAFs can also reduce activated T cell infiltration of the tumour site and secrete a variety of cytokines, including TGF-b that is associated with EMT (16,60). This can promote the migration of immunosuppressive inflammatory cells such as regulatory T cells (Treg), myeloid-derived suppressor cells (MDSCs), and tumour-associated macrophages (TAMs) through the CXC motif chemokine ligand (CXCL)-CXC chemokine receptor (CXCR) axis (9,61).…”

“…CTGF is a profibrotic extracellular protein with an abundantly elevated expression in PC (16). CTGF is mediated by chemokine signalling, which promotes fibrosis and collagen deposition, which in turn causes cancer progression and metastasis (87,88).…”

Therapeutic Intervention in Cancer by Isoliquiritigenin from Licorice: A Natural Antioxidant and Redox Regulator

“…Unfortunately, chemotherapy is often associated with many drawbacks, including chemoresistance and serious systemic side effects [ 1 ]. Thus, signal transduction target therapy, immunotherapy, stem-cell therapy, modulation of the stroma, and inhibition of cancer metabolism have been emerging for the treatment of PDAC [ 2 , 3 ]. Among different tumorigenic mechanisms, metabolic dysregulation has largely contributed to the formation and progression of pancreatic cancer, and it offers new insights into the development of novel adjuvants for the modulation of the associated mechanism.…”