The cross-talk between the macro and micro-environment in precursor lesions of pancreatic cancer leads to new and promising circulating biomarkers

Abstract

Pancreatic cancer (PC) is a clinically challenging tumor to combat due to its advanced stage at diagnosis as well as its resistance to currently available therapies. The absence of early symptoms and known detectable biomarkers renders this disease incredibly difficult to detect/manage. Recent advances in the understanding of PC biology have highlighted the importance of cancer-immune cell interactions, not only in the tumor micro-environment but also in distant systemic sites, like the bone marrow, spleen and circulating immune cells, the so-called macro-environment. The response of the macro-environment is emerging as a determining factor in tumor development by contributing to the formation of an increasingly immunogenic micro-environment promoting tumor homeostasis and progression. We will summarize the key events associated with the feedback loop between the tumor immune micro-environment (TIME) and the tumor immune macroenvironment (TIMaE) in pancreatic precancerous lesions along with how it regulates disease development and progression. In addition, liquid biopsy biomarkers capable of diagnosing PC at an early stage of onset will also be discussed. A clearer understanding of the early crosstalk between micro-environment and macro-environment could contribute to identifying new molecular therapeutic targets and biomarkers, consequently improving early PC diagnosis and treatment.

Keywords: Circulating biomarkers; Immune landscape; Macro-environment; Micro-environment; Pancreatic cancer.

Fig. 1

Evolution of tumor micro-environment composition from most common pancreatic cancer precursor lesions to PC considering mutational landscape. Progression from pancreatic cancer precursor lesions to PC is characterized by an high dynamism involving both multiple genetic mutations and heterogeneity of tumor micro-environment. In details, KRAS, CDKN2A, TP53 and SMAD are the key mutations in both PanINs and IPMNs. In PanIN, CDKNA and KRAS mutations are observed in the earliest stages, whereas TP53 and SMAD arise later. Other mutations cooperate to drive disease progress, such as YAP1 and ARID1, frequently observed in PanIN and MUCA5C, GNAS, RNF43 and KLF4, more selective for IPMN. The heterogeneity of tumor micro-environment is determined by a complex signaling networks between tumor, stromal and immune cells that leas to tumor progression of PanIN, along IPMN to cancer. Beyond cancer associated fibroblast (CAFs), pancreatic stellate cells (PSCs), and other stromal components, myeloid progenitors and haematopoietic stem cells are some of the main players involved in this cross-talk. As a result of cytokines and growth factors released by the tumor, these cells undergo an altered differentiation process, acquiring immunosuppressive properties capable of counteracting the anti-tumor immune response. In the figure are reported the main actor involved in the cross-talk between TIME and TIMaE, as listened below: pancreatic stellate cells (PSCs), myeloid derived suppressor cells (MDSCs), polymorphonucleated myeloid derived suppressor cells (PMN-MDSCs), mesenchymal stem cells (MSCs), tumor associated macrophages (TAMs) and BM-derived endothelial progenitor cells (BM-EPCs)

Fig. 2

The sinergic crosstalk between macro and microenvironment in pancreatic cancer. Mobilization of hematopoietic stem and progenitor cells from the bone marrow and spleen to tumor site represents a key immune regulatory event in pancreatic cancer and early stages of disease. Growth factors released by pancreatic tumor cells (VEGF, Angiopoietin-1, IL-6, IL-8) promote a dysregulated hematopoiesis leading to mobilization of stem cells (BM-derived endothelial progenitor cells (BM-EPCs), mesenchymal stem cells (MSCs), in tumor microenvironment and their differentiation into immunosoppressive cells populations. Complement component C5a and C5b-9/MAC, sphingosine 1-phosphate (S1F) and Hepatocyte growth factor (HGF) are highly correlated with MSC mobilization. MDSC mobilization from bone marrow and spleen occur at early stage of the disease and is promoted by several tumor factors such as IL-6, CCL-2, IL-10, GM-CSF, G-CSF, SCF and CCL2. CCR2 mediated signaling drive monocyte mobilization from BM and differentiation in TAM. Pancreatic stellate cells (PCS) differentiate from BM progenitor cells and exert a key funtional role in early stage and cancer progression. Some of the factors that are engaged in the tumour-bone marrow cross-talk are currently recognised as diagnostic markers in pancreatic cancer. These include IL-6, VEGF, GM-CSF, G-CSF and TNF-a. In addition to date several inflammatory citokines (IL-17, IL-2R, IL-8, 1L-10) metabolites, miRNA, exosomes, cfDNA and CTCs rapresenting to date the promising blood biomarkers in early pancreatic cancer lesions and tumor