Pancreatic Cancer and Cellular Senescence: Tumor Microenvironment under the Spotlight

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has one of the most dismal prognoses of all cancers due to its late manifestation and resistance to current therapies. Accumulating evidence has suggested that the malignant behavior of this cancer is mainly influenced by the associated strongly immunosuppressive, desmoplastic microenvironment and by the relatively low mutational burden. PDAC develops and progresses through a multi-step process. Early in tumorigenesis, cancer cells must evade the effects of cellular senescence, which slows proliferation and promotes the immune-mediated elimination of pre-malignant cells. The role of senescence as a tumor suppressor has been well-established; however, recent evidence has revealed novel pro-tumorigenic paracrine functions of senescent cells towards their microenvironment. Understanding the interactions between tumors and their microenvironment is a growing research field, with evidence having been provided that non-tumoral cells composing the tumor microenvironment (TME) influence tumor proliferation, metabolism, cell death, and therapeutic resistance. Simultaneously, cancer cells shape a tumor-supportive and immunosuppressive environment, influencing both non-tumoral neighboring and distant cells. The overall intention of this review is to provide an overview of the interplay that occurs between senescent and non-senescent cell types and to describe how such interplay may have an impact on PDAC progression. Specifically, the effects and the molecular changes occurring in non-cancerous cells during senescence, and how these may contribute to a tumor-permissive microenvironment, will be discussed. Finally, senescence targeting strategies will be briefly introduced, highlighting their potential in the treatment of PDAC.

The Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis

“…Senescence has long been considered an important mechanism to prevent tumorigenesis, thus acting as a guardian of homeostasis, which agrees with p16INK4A, p14ARF/p19ARF, and p21 knockout mouse models. However, more recent data allow to draw a more differentiated picture of senescence and the SASP in tumor initiation and progression (reviewed in [ 200 , 201 , 202 , 203 , 204 ]). Organ and tissue homeostasis, however, do not only play a role in cancer prevention, but represent the central organizing principle of physiology and pathophysiology [ 205 ].…”

Integrated analysis of senescence-associated genes in pancreatic ductal adenocarcinoma

“…PDAC is a disease with a dire prognosis and one of the few cancers with a rising incidence (Gheorghe et al, 2020). Growing Frontiers in Genetics frontiersin.org evidence suggests that its malignant behavior is largely influenced by the associated strong immunosuppression, relatively low mutational burden, and desmoplastic microenvironment (Cortesi et al, 2021). During the early stages of tumorigenesis, cancer cells must shed the effects of cellular senescence, which slows proliferation and promotes immune-mediated clearance of precancerous cells.…”

Precision Medicine in Head and Neck Cancers: Genomic and Preclinical Approaches

“…HNCs are solid tumours, a group of malignancies that take advantage of the crosstalk between cell and non-cell components [ 128 , 129 ]. These interactions regulate molecular processes involved in cancer progression, migration, drug sensitivity, and proliferation, taking part in the development of a protumorigenic microenvironment [ 104 , 130 , 131 ]. Primary cultures partially mimic tumour microenvironment features.…”