Paracrine and cell autonomous signalling in pancreatic cancer progression and metastasis

Abstract

Pancreatic ductal adenocarcinoma (PDAC) shows remarkable propensity to metastasize. This predilection to escape from the primary tumor is driven by paracrine and autocrine mechanisms that guide cancer cells through a multi-step process concluding with colonization in distant tissues. Although cell-intrinsic features support the metastatic ability of cancer cells, permissive microenvironments within the primary organ and at sites of distant metastasis may be rate-limiting. Identification of cancer cell-extrinsic factors that regulate formation of these environments lend new therapeutic targets for intervening on the metastatic cascade. In addition, the bipolar, yet fundamental, role of the immune system in the metastatic process presents therapeutic opportunities. Herein, we review the current knowledge of the metastatic cascade in PDAC, and propose that genomically stable determinants of metastasis (e.g. the pro-metastatic niche and immune system) are actionable targets for preventing, containing, and treating metastasis in PDAC.

Keywords: Cancer; Clinical trials; Immune evasion; Immunosurveillance; Immunotherapy; Inflammation; Macrophages; Metastasis; Neutrophils; Pancreatic ductal adenocarcinoma; T cells; Therapeutic resistance; Treatment paradigms; Tumor microenvironment; Vaccines.

Fig. 1

Five-year survival for patients with pancreatic ductal adenocarcinoma diagnosed with localized, regional (i.e. lymph node involvement), or distant (i.e. metastatic to other organs) disease. Graph is based on mortality data from the National Center for Health Statistics reported for 2006 , 2012 , and 2019 by the American Cancer Society. Numbers associated with histogram bars indicate percent of patients alive at ≥5 years after diagnosis.

Fig. 2

Graphical representation of the metastatic cascade in pancreatic ductal adenocarcinoma. Metastasis is a multi-step process involving signals that support cancer cell dissemination (steps 1–5) and that condition distant organs (steps 6 and 7) for increased permissiveness of disseminated cancer cells (DCC). During metastasis, malignant epithelial cells detach from the basement membrane (step 1), invade into the surrounding stroma (step 2) and intravasate into the bloodstream (step 3) leading to dissemination (step 4) and subsequent, lodging in a distant organ (step 5), such as the liver. Concurrently, primary tumors release factors (step 6) that promote the development of a pro-metastatic niche environment in a distant organ (step 7). DCCs then extravasate (step 8) into the parenchyma of the distant organ where they seed (step 9). Thereafter, DCCs either lie dormant awaiting appropriate awakening signals or proceed to colonize the distant tissue.

Fig. 3

Approaches for intervening on the metastatic process. Shown is a schematic depicting the formation of a pro-metastatic niche in a distant organ (the liver is displayed as an example). This process can be facilitated by tumor-derived factors which initiate formation of the niche environment and in doing so, support seeding and colonization by disseminated cancer cells. The metastatic process can be derailed in several ways: Approach 1, prevent or reverse the niche formation in a distant organ; Approach 2, contain micro-metastases to prevent their outgrowth; and Approach 3, treat macro-metastases.

Fig. 4

Graphical representation of determinants of the metastatic process. Metastasis is determined by multiple cancer cell-intrinsic and -extrinsic properties that converge to establish the metastatic ability of pancreatic cancer cells. These determinants include cancer cell genetics, properties of the tumor microenvironment, systemic inflammation, evidence of cancer cell dissemination based on peripheral blood detection of circulating tumor material, the presence of pro-metastatic niche environments in distant organs, and detection of macro-metastatic lesions by computed tomography, magnetic resonance, and positron emission tomography imaging. Together, these surrogate markers combine to create a proposed metastasis score, or likelihood of distant spread of disease. Abbreviations: CRP, c-reactive protein; CT, computed tomography; CTC, circulating tumor cell; CTM, circulating tumor material; IL, interleukin; MR, magnetic resonance; NLR, neutrophil-to-lymphocyte ratio; PET, positron emission tomography; SAA, serum amyloid A; TIMP1, tissue inhibitor of metalloproteinase 1; TME, tumor microenvironment.