Tumor cell dormancy

Abstract

Metastasis is the primary cause of death in cancer patients and current treatments fail to provide durable responses. Efforts to treat metastatic disease are hindered by the fact that metastatic cells often remain dormant for prolonged intervals of years, or even decades. Tumor dormancy reflects the capability of disseminated tumor cells (DTCs), or micrometastases, to evade treatment and remain at low numbers after primary tumor resection. Unfortunately, dormant cells will eventually produce overt metastasis. Innovations are needed to understand metastatic dormancy and improve cancer detection and treatment. Currently, few models exist that faithfully recapitulate metastatic dormancy and metastasis to clinically relevant tissues, such as the bone. Herein, we discuss recent advances describing genetic cell-autonomous and systemic or local changes in the microenvironment that have been shown to endow DTCs with properties to survive and eventually colonize distant organs.

Keywords: Breast cancer; Cancer; Dormancy; Latency; Metastasis.

Figure 1

The temporal course of cancer metastasis. Metastatic relapse may occur within months, years or decades after primary tumor diagnosis, removal, and systemic treatment. Different cancer types exhibit variability in length of the latency: short for lung cancer (red), middle for colon cancer and ER− breast cancer (yellow), and long for prostate cancer and ER+ breast cancer (blue). Dashed line indicates threshold of detection symptomatic metastases.

Figure 2

The temporal course of breast cancer metastasis. ER− breast cancer subtypes metastases typically occur within 5 years after primary tumor diagnosis (grey) whereas ER+ can relapse early (before 5 years) or late, up to decades after initial diagnosis (orange). Dashed line indicates clinical threshold for early and late relapse.

Figure 3

The metastatic cascade. Metastasis progresses through the sequence of steps that promote malignant cells, from primary tumor, to disseminate and colonize distant organ. Acquisition of each step is driven by specific cellular functions. Cascade steps are indicated in grey blocks, cell autonomous functions important in each step in black, circulating tumor cell in green, and disseminated tumor cell in blue.

Figure 4

Mechanisms of cancer dormancy. Metastatic dormancy is induced and maintained by cellular (yellow), angiogenic (blue) and immune (red) mechanisms, which contribute to dormancy in different proportions. Solitary cell dormancy (cellular dormancy), defined as arrest in the cell cycle, is mediated by different signaling pathways including PI3K‐AKT low signaling and high p38 over ERK activity. In tumor mass dormancy (right) proliferation is balanced by cell death due to lack of blood supply and immune surveillance. Ki67⁻ indicates an arrested cell, Ki67⁺ states for a proliferating cell, Casp+ depicts an apoptotic cell.

Figure 5

The metastatic niches in the bone marrow. In order to survive, DTC reside in different compartments in the bone marrow, so called niche. Niche occupancy depends on the pro‐survival interactions between metastatic cells (orange) and host stroma composed of different cell types of bone marrow (red or blue). In perivascular niche, sprouting neovasculature promotes micrometastatic outgrowth by secretion of periostin by endothelial cells (red) and Wnt signaling activation in metastatic cells. Mesenchymal cells in HSC niche (blue) release chemokine CXCL12 that, by CXCR4 receptor binding in metastatic cells, signals through PI3K‐AKT pathway. SRC kinase alterations in DTC amplify AKT pathway activation. DTC can also interact with osteogenic cells (blue) by formation of heterotypic adherens junctions between N‐cadherin and expressed by metastatic cells E‐cadherin. Therefore, mTOR signaling is activated promoting tumor growth.

Figure 6

The bone metastasis vicious cycle. During the osteolytic cycle, metastatic cells in the bone microenvironment produce molecules that stimulate osteoclastic bone resorption directly by MMP and VCAM1 (grey), or indirectly through osteoblast activation by osteoblastic factors (orange). Activated osteoblasts secret osteoclastic factors (blue) mainly RANKL to promote bone degradation by proteases and collagenases (yellow). The consequence of increased resorption is the release of growth factors from the bone matrix (grey) that feed back to the metastatic cells, further stimulating their growth. Ca²⁺ that stands for calcium ions.