Oncogenic and Non‐Malignant Pancreatic Exosome Cargo Reveal Distinct Expression of Oncogenic and Prognostic Factors Involved in Tumor Invasion and Metastasis

Abstract

Exosomes are small extracellular membrane vesicles important in intercellular communication, with their oncogenic cargo attributed to tumor progression and pre‐metastatic niche formation. To gain an insight into key differences in oncogenic composition of exosomes, human non‐malignant epithelial and pancreatic cancer cell models and purified and characterized resultant exosome populations are utilized. Proteomic analysis reveals the selective enrichment of known exosome markers and signaling proteins in comparison to parental cells. Importantly, valuable insights into oncogenic exosomes (362 unique proteins in comparison to non‐malignant exosomes) of key metastatic regulatory factors and signaling molecules fundamental to pancreatic cancer progression (KRAS, CD44, EGFR) are provided. It is reported that oncogenic exosomes contain factors known to regulate the pre‐metastatic niche (S100A4, F3, ITGβ5, ANXA1), clinically‐relevant proteins which correlate with poor prognosis (CLDN1, MUC1) as well as protein networks involved in various cancer hallmarks including proliferation (CLU, CAV1), invasion (PODXL, ITGA3), metastasis (LAMP1, ST14) and immune surveillance escape (B2M). The presence of these factors in oncogenic exosomes offers an understanding of select differences in exosome composition during tumorigenesis, potential components as prognostic and diagnostic biomarkers in pancreatic cancer, and highlights the role of exosomes in mediating crosstalk between tumor and stromal cells.

Extracellular Vesicle-Dependent Cross-Talk in Cancer—Focus on Pancreatic Cancer

“…Moreover, oncogenic exosomes contain factors known to regulate the premetastatic niche (S100A4, F3, ITGβ5, and ANXA1), clinicallyrelevant proteins which correlate with poor prognosis (CLDN1, MUC1) as well as protein networks involved in various cancer hallmarks including proliferation (CLU, CAV1), invasion (PODXL, ITGA3), metastasis (LAMP1, ST14) and immune surveillance escape (B2M). This study highlights the modification of exosome protein content during tumorigenesis and suggests putative components as prognostic and diagnostic biomarkers in pancreatic cancer (46).…”

“…Differences in composition between exosomes from human non-malignant epithelial and pancreatic cancer cells were analyzed by Emmanouilidi et al (46). Proteomic analysis reveals the selective enrichment of known exosome markers and also signaling proteins involved in pancreatic cancer progression (KRAS, CD44, and EGFR) in oncogenic exosomes compared to exosomes from non-malignant cells.…”

Cancer Extracellular Vesicles: Next-Generation Diagnostic and Drug Delivery Nanotools

“…EEVs may have a high level of pro-angiogenesis molecules, promoting endothelial cell proliferation and the survival and differentiation of fibroblasts into myofibroblasts, leading to tumor vascularization. They can also enhance vessels' permeability, leading to tumor cell diffusion and metastasis [112]. Interest has grown in adipose-derived stem cells in the TME; preclinical studies suggested that adipose-derived stem cells could be a potential tumor promoter, supporting tumor progression and activating several intracellular signals [113].…”

Extracellular Vesicles and Tumor-Immune Escape: Biological Functions and Clinical Perspectives

“…It has now been widely demonstrated that EVs derived from tumor cells (TEVs) can promote tumor-mediated immune suppression creating a tumor-friendly microenvironment [3,4]. Many studies are specifically focused on small extracellular vesicles (sEVs), to date also named exosomes, a well-characterized subtype of EVs playing a pleiotropic role in different key processes of tumor formation and progression; in fact, EVs are involved in tumor microenvironment (TME) remodeling as angiogenesis [5][6][7], invasion [8,9], metastasis [10][11][12], and resistance to therapies [13,14]. sEVsare nano-sized (40-100 nm) membrane-delimited vesicles that are secreted by almost all cell types under both normal and pathological conditions.…”