Metastatic disease represents a main cancer-related cause of death, which means the development of metastases -other tumors in other districts of the body- after surgical primary tumor resection, even though at the time of surgery careful examination excluded the presence of metastatic lesions.
Cell quiescence in metastatic spread. Recent hypotheses suggest that metastases develop from single latent metastatic cells that have disseminated away from the original primary tumor site, successively entering a so-called “quiescent” state, not proliferating until conditions become favorable to start proliferating and give rise to metastases. The non-proliferating, quiescent state is maintained due to a combination of intrinsic cell reasons and microenvironmental factors. Indeed, the immune system (the microenvironment) has been shown to have a role in keeping the latent quiescent state of the metastatic cells.
ER stress in establishment of quiescent metastases. A recent research demonstrates that in pancreatic cancer, disseminated cancer cells are selected by the immune system (particularly by the T cell subtype) that eliminates those expressing the MHCI protein complex, leaving untouched those lacking MHCI expression, that instead remain quiescent (MHCI has a crucial role in immune system –specifically T cells- activation. See https://archive-sciencewhatelse.jimdo.com/immune-system/ ). Quiescent cells that due to the absence of MHCI are able to survive T cells-mediated depletion will later form metastases. MHCI expression, and the consequent resistance of disseminated cancer cells to immune-mediated clearance and the establishment as latent metastases, is induced by ER stress*: ER stress represents thus the intrinsic cell factor that, combined with microenvironmental aspects, keeps disseminated cells quiescent and resistant to immunity.
Metastases quiescence release. To trigger proliferation and establish overt metastases, firstly, ER stress must be resolved (thus leading to MHCI re-expression) and secondly, T cells must be depleted (otherwise, they would remove the cells expressing MHCI, as they did in the first place).
Normally, cells experiencing ER stress initiate a specific pathway to resolve ER stress, involving the activation of a protein called IRE1alpha. These cells overcoming ER stress, re-expressing MHCI, become target of immune suppression. If the immune system was not ready to intervene, this subpopulation would lead to insurgence of metastases).
However, if IRE1alpha pathway is not activated and ER stress is not relieved, cells will assume that quiescent phenotype making them escape immune suppression: no immune suppression means no macrometastases formation, but single latent metastases existence that, as soon as the optimal situation is established, will evolve into metastases.
Reference. Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases. Pommier A, Anaparthy N, Memos N, Kelley ZL, Gouronnec A, Yan R, Auffray C, Albrengues J, Egeblad M, Iacobuzio-Donahue CA, Lyons SK, Fearon DT. Science 2018.
*ER (endoplasmic reticulum) is an organelle located inside the cell, with several key functions for cell physiology, including correct protein folding and maturation. Improperly folded proteins cannot be processed and accumulate in the ER, causing the so called ER stress:this organelle is no more able to maintain the homeostasis.