Role of the Microenvironment in Liver Metastasis: From Pre- to Prometastatic Niches

Abstract

Liver metastases remain a major barrier to successful management of malignant disease, particularly for cancers of the gastrointestinal tract but also for other malignancies, such as breast carcinoma and melanoma. The ability of metastatic cells to survive and proliferate in the liver is determined by the outcome of complex, reciprocal interactions between tumor cells and different local resident subpopulations, including the sinusoidal endothelium, stellate, Kupffer, and inflammatory cells that are mediated through cell-cell and cell-extracellular matrix adhesion and the release of soluble factors. Cross-communication between different hepatic resident cells in response to local tissue damage and inflammation and the recruitment of bone marrow cells further enhance this intercellular communication network. Both resident and recruited cells can play opposing roles in the progression of metastasis, and the balance of these divergent effects determines whether the tumor cells will die, proliferate, and colonize the new site or enter a state of dormancy. Moreover, this delicate balance can be tilted in favor of metastasis, if factors produced by the primary tumor precondition the microenvironment to form niches of activated resident cells that promote tumor expansion. This review aims to summarize current knowledge on these diverse interactions and the impact they can have on the clinical management of hepatic metastases. Clin Cancer Res; 22(24); 5971-82. ©2016 AACR.

Partially exhausted tumor-infiltrating lymphocytes predict response to combination immunotherapy

“…Preclinical data suggest that activated CD8 + T cells can be selectively deleted in the liver (29) and that liver tolerance (30) is operational in allotransplantation. Further studies in other tumor types and animal models may reveal additional information about the mechanism of liver metastasis-induced tolerance (31). The effect of female sex on reduced response rate to PD-1 has been recently reported (22,32).…”

Molecular Pathways: Targeting the Microenvironment of Liver Metastases

“…These processes of liver metastasis is facilitated by two critical niches, namely the pre-metastatic niche driven by factors secreted by the primary tumor that in turn, recruit non-parenchymal cells including Kupffer cells (KC), hepatic stellate cells (HepSC), myeloid-derived suppressor cells (MDSC) and neutrophils, and the post-tumor invasion niche, which develops following tumor cell entry into the liver and can be characterized by four key phases (i) a microvascular phase (ii) an extravascular pre-angiogenic phase (iii) an angiogenic phase and (iv) the growth phase (detailed below and reviewed extensively in (5–7)). With the exception of the angiogenic phase, the potential therapeutic benefit of targeting the ME at each of these phases, has not been adequately explored.…”

“…These phases were extensively reviewed elsewhere (5–7) and are briefly summarized here as background for subsequent sections.…”

A system for detecting high impact-low frequency mutations in primary tumors and metastases

“…S2). Phospholipase A2 group IVE ( PLA2G4E ; mutated in liver metastases) mediates the activity of migration inhibitory factor (MIF), a major factor required for establishing liver metastasis 5, 44 . ZP3 is expressed mostly in oocytes and sperm and relevance of its mutation in liver metastasis is unknown 32, 50 .…”

“…After initial proof-of-concept studies in six primary breast cancer samples, we extended the study to metastatic samples. By propagating and sequencing liver metastasis of breast, colon, melanoma and spindle cell carcinoma of the abdomen, we determined that mutations common in liver metastasis of these four types of cancers were an integral part of a signaling network involving migration inhibitory factor (MIF)-mediated glucocorticoid regulation and/or Notch signaling, previously shown to be essential for establishing liver metastasis 5 . Furthermore, we detected rare mutations in brain metastases, suggesting that our approach can be applied to detect both common and rare mutations in metastases of various cancers.…”