The hepatic microenvironment essentially determines tumor cell dormancy and metastatic outgrowth of pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed when liver metastases already emerged. This study elucidated the impact of hepatic stromal cells on growth behavior of premalignant and malignant pancreatic ductal epithelial cells (PDECs). Liver sections of tumor-bearing KPC mice comprised micrometastases displaying low proliferation located in an unobtrusive hepatic microenvironment whereas macrometastases containing more proliferating cells were surrounded by hepatic myofibroblasts (HMFs). In an age-related syngeneic PDAC mouse model livers with signs of age-related inflammation exhibited significantly more proliferating disseminated tumor cells (DTCs) and micrometastases despite comparable primary tumor growth and DTC numbers. Hepatic stellate cells (HSC), representing a physiologic liver stroma, promoted an IL-8 mediated quiescence-associated phenotype (QAP) of PDECs in coculture. QAP included flattened cell morphology, Ki67-negativity and reduced proliferation, elevated senescence-associated β galactosidase activity and diminished p-Erk/p-p38-ratio. In contrast, proliferation of PDECs was enhanced by VEGF in the presence of HMF. Switching the micromilieu from HSC to HMF or blocking VEGF reversed QAP in PDECs. This study demonstrates how HSCs induce and maintain a reversible QAP in disseminated PDAC cells, while inflammatory HMFs foster QAP reversal and metastatic outgrowth. Overall, the importance of the hepatic microenvironment in induction and reversal of dormancy during PDAC metastasis is emphasized.

Metastasis-associated fibroblasts promote angiogenesis in metastasized pancreatic cancer via the CXCL8 and the CCL2 axes

“…This implies that the ratio of cells in the tumour microenvironment shifted to the more pro-tumorigenic myofibroblasts (i.e. MAFs), and their potential to promote cancer proliferation and sunitinib resistance 13,22,24,31 .…”

“…CXCL8 is a major pro-angiogenic factor [53][54][55][56][57] , functioning through its receptor CXCR2 58,59 . In addition to its angiogenic functions, CXCL8 is also involved with maintaining hepatic metastatic lesions in an occult form, so long as the liver is uninflamed and hepatic stellate cells are not differentiating into MAFs 31 . Overall, the CXCL8 axis is a therapeutic target in PDAC and blockading the axis reduces pancreatic cancer stem cells, invasion and metastases 51 .…”

Impact of the Monocarboxylate Transporter-1 (MCT1)-Mediated Cellular Import of Lactate on Stemness Properties of Human Pancreatic Adenocarcinoma Cells

“…Thus, concepts have been already discussed that consider disrupting the metabolic coupling between cancer and stroma cells as pivotal in breaking resistance to conventional therapies [57][58][59][60]. Such a treatment might have great potential in a stroma rich tumor such as PDAC, suppressing particularly stem cell-like and dormant tumor cell clones that drive recurrence and metastasis formation [61]. However, the environmental context in which MCT1 exerts its effects on tumor growth seems to be an important issue.…”

What is the storage effect, why should it occur in cancers, and how can it inform cancer therapy?

“…The growth of new blood vessels provokes sufficient change to the microenvironment to reactivate breast cancer cells 39,40 . Age-related inflammation promotes the outgrowth of dormant cells in pancreatic ductal adenocarcinoma liver metastases 41 . PACCS emerge from quiescence after removal of chemotherapy and they do so after a range of quiescence durations (Sarah Amend, PhD, email communication, February 2020).…”