Cancer Cell Dormancy in Metastasis

Abstract

Recurrent metastasis following extended periods of disease-free survival remains a common cause of morbidity and mortality for many cancer patients. Recurrence is thought to be mediated by tumor cells that escaped the primary site early in the disease course and colonize distant organs. In these locations, cells adapt to the local environment, entering a state of longterm dormancy in which they can resist therapy. Then, through mechanisms that are poorly understood, a proportion of these cells are reactivated and become proliferative, forming lethal metastases. Here, we discuss disseminated tumor cell dormancy in recurrent metastasis. We discuss mechanisms known to control entrance of cells into dormancy, highlighting the relevant microenvironments or "niches" in which these cells reside and mechanisms known to be involved in dormant cell reactivation. Finally, we consider emerging therapeutic approaches aimed at eradicating residual disease and preventing metastatic relapse.

Mathematical modeling of metastasis, a feasible way to detect the weakness

“…At this stage of metastasis, dormant tumors (L) in secondary sites also play an important role in tumor regression after surgical recession [49] . In addition, cells when leaving the latency (R) show a more aggressive behavior [50] . This is why self-organization at this stage makes resistance to therapy more pronounced.…”

Technical Advancements for Studying Immune Regulation of Disseminated Dormant Cancer Cells

“…According to a recent analysis, the proportion of cancer deaths with metastases as contributing cause, ranged from 9.3% for CNS cancers to 90.4% and 80.2% for ovarian and colon cancer, respectively ( 1 , 2 ). Metastases can be detected in concomitance with the primary tumor (synchronous) or at a later stage (metachronous).…”

“…Although most tumors cover the same steps of metastatic dissemination (i.e., extravasation, dissemination through blood or lymphatics, intravazation, and establishment in the metastatic niche), the time required to form overt lesions significantly differs according to the tissue of origin and cancer subtypes. While breast, prostate, renal cell cancers, as well as sarcomas and melanomas show long latency and the time required to develop metachronous metastasis might reach 15 years, 85% of relapses from colon cancer are detected within 3 years (medium latency), and lung cancers often spread at distant sites within a few weeks (short latency) ( 1 , 3 – 5 ). When the time required for a DCC to form an overt metastasis after the removal of the primary tumor is long (arbitrarily usually set as 5 years), latency is often referred to as “dormancy”.…”

“…The fate of disseminated cells is driven by a combination of cell intrinsic, extrinsic and stochastic events ( 1 ). Cell intrinsic programs involve oncogenes and tumor suppressors, membrane proteins (integrins, receptors etc…), intracellular components (such as cytoskeletal proteins and mechanotransducers), signaling pathways and sensors that integrate genetic and microenvironmental inputs and translate them into cellular processes.…”

Curcumin derivative C212 inhibits Hsp90 and eliminates both growing and quiescent leukemia cells in deep dormancy

“…These drugs, e.g., doxorubicin, paclitaxel and topotecan, are ineffective against slow-growing or quiescent cancer cells that do not undergo active DNA replication and cell division [4,5]. Accordingly, quiescent cancer cells, including but not limited to cancer stem cells, escape conventional chemotherapies; they often reemerge after a period of dormancy, causing cancer relapse and metastasis that are exceedingly difficult to treat and lead to high patient mortality [6][7][8].…”