Mechanisms of Cancer Cell Dormancy--Another Hallmark of Cancer?

Abstract

Disease relapse in cancer patients many years after clinical remission, often referred to as cancer dormancy, is well documented but remains an incompletely understood phenomenon on the biologic level. Recent reviews have summarized potential models that can explain this phenomenon, including angiogenic, immunologic, and cellular dormancy. We focus on mechanisms of cellular dormancy as newer biologic insights have enabled better understanding of this process. We provide a historical context, synthesize current advances in the field, and propose a mechanistic framework that treats cancer cell dormancy as a dynamic cell state conferring a fitness advantage to an evolving malignancy under stress. Cellular dormancy appears to be an active process that can be toggled through a variety of signaling mechanisms that ultimately downregulate the RAS/MAPK and PI(3)K/AKT pathways, an ability that is preserved even in cancers that constitutively depend on these pathways for their growth and survival. Just as unbridled proliferation is a key hallmark of cancer, the ability of cancer cells to become quiescent may be critical to evolving malignancies, with implications for understanding cancer initiation, progression, and treatment resistance.

Figure 1. Biological Mechanisms of Cancer Dormancy

A) Clinical dormancy is depicted in the graph as the period of time after treatment when residual malignant cells become detectable either as recurrent local or metastatic disease. B) Cancer dormancy can be distinguished physiologically as cellular dormancy or tumor mass dormancy (rate of proliferation is balanced by rate of apoptosis). Progression of cancer occurs in cellular dormancy when individual dormant malignant cells re-enter the cell cycle. Likewise, progression in tumor mass dormancy occurs when an angiogenic switch occurs or when tumor cells evade immune surveillance, after which the equilibrium between proliferation and apoptosis shifts in favor of the former.

Figure 2. Pathways of cellular dormancy

Cellular dormancy is governed by a combination of external and internal cues. Current literature supports the role of integrin receptor signaling as a pivotal event that leads to the activation of Ras-ERK/MAPK and PI(3)K-AKT pathways, thereby maintaining cell cycle progression. Down-regulation of integrin signaling is a critical driver of cellular dormancy and can be influenced by the composition of extracellular matrix. Intrinsic signaling through the stress pathway uPAR/p38 can also shift the balance towards cellular dormancy through downregulation of the MAPK pathway.