Metastases and cancer recurrence are the major causes of cancer death. They represent one of the major challenges in oncology. Why do some cancers come back many years after treatments had eliminated all signs of the disease? The answer involves a process called “metastasis” whereby cancer cells can leave their primary sites and travel through the circulation to various distant organs, where they lodge as disseminated cancer cells (DCCs) even during the early and asymptomatic stages of tumor progression and then enter a sleeping, or dormant, state. Tumor cell dormancy refers to the reversible quiescent state, where the cell cycle arrests at the G0/G1 phase. In this state, dormant cells avoid detection, and escape chemotherapy and immune surveillance. Once reactivated, these cells can proliferate quickly to a tumor mass and overt metastases.
Metastasis is an extremely inefficient process constituted by consecutive harsh steps. The mobilized cancer cells have to cope with various kinds of stresses to successfully translocate from the primary site to distal organs and colonize there. To achieve that, cancer cells often coordinate their intrinsic gene expression network with the extrinsic cellular microenvironment to confront the physical, chemical, and biological challenges during the metastatic journey.
There is clinical evidence to support the existence of dormant cancer cells in many common cancers, including breast, prostate, lung, colon, and kidney cancers, as well as melanoma and cancers of the blood, such as leukemia and multiple myeloma. Some of this evidence has come from rare instances of people developing cancer after receiving an organ transplant from a donor who had had cancer in the past but was thought to be in remission at the time of the donation. Genetic tests confirmed that the tumors in the recipients matched the donor’s cancer.
What causes disseminated cancer cells to enter, and then to leave, a dormant state is not known. Recent studies of tumor dormancy have yielded clues that scientists believe could one day help them find ways to prevent metastases, which account for most cancer deaths.
According to Joan Massagué, Ph.D., chief scientific officer of Memorial Sloan Kettering Cancer Center, who studies cancer dormancy, “Disseminated cancer cells are a special subset of cancer cells,” “They have the features of what we call primitive progenitor cells, a family of cells that can generate healthy tissue and repair damaged tissue.” But rather than producing healthy tissue, dormant cancer cells have the potential to regenerate tumors, often at a distance from a primary tumor, Dr. Massagué added.
Dormant cancer cells also have the ability to evade detection by the immune system. Dormancy may therefore be a kind of protective state, researchers say. “Tumor cells have developed mechanisms that allow the dormant cells to hide from immune cells, a phenomenon sometimes known as cloaking,” said Li Yang, Ph.D., of NCI’s Center for Cancer Research, who studies dormancy. “This means the dormant tumor cells cannot be recognized and then be destroyed.”
Two main strategies have been proposed by Max Wicha, M.D., of the University of Michigan Rogel Cancer Center for addressing the threat posed by dormant tumor cells. One approach would identify and kill dormant cancer cells, perhaps by making the cells sensitive to attack by immune cells. Another approach would keep disseminated cancer cells in a dormant state, ensuring that they could never cause harm.
Julio Aguirre-Ghiso, Ph.D., director of the Cancer Dormancy Institute at the Montefiore Einstein Comprehensive Cancer Center in New York, has also been exploring ways to intervene early to prevent a metastatic recurrence. His team recently identified an experimental drug that targets a signaling pathway that dormant cancer cells need to stay alive during their hibernation. The drug, called HC-5404, prevented dormant cancer cells in mice from causing metastases. The treatment was subsequently tested in patients with advanced cancers, and the Food and Drug Administration has granted HC-5404 Fast Track designation, which can speed up the review of new therapies.
Because the knowledge of the biology, origins, and heterogeneity of DCCs is still limited for most cancer types, research efforts to profile these cells are of utmost importance for identifying patients at risk of relapse, reducing overtreatment and designing effective therapeutic strategies.
