The dormancy dilemma: quiescence versus balanced proliferation

Abstract

Metastatic dissemination with subsequent clinical outgrowth leads to the greatest part of morbidity and mortality from most solid tumors. Even more daunting is that many of these metastatic deposits silently lie undetected, recurring years to decades after primary tumor extirpation by surgery or radiation (termed metastatic dormancy). As primary tumors are frequently curable, a critical focus now turns to preventing the lethal emergence from metastatic dormancy. Current carcinoma treatments include adjuvant therapy intended to kill the cryptic metastatic tumor cells. Because such standard therapies mainly kill cycling cells, this approach carries an implicit assumption that metastatic cells are in the mitogenic cycle. Thus, the pivotal question arises as to whether clinically occult micrometastases survive in a state of balanced proliferation and death, or whether these cells undergo at least long periods of quiescence marked by cell-cycle arrest. The treatment implications are thus obvious--if the carcinoma cells are cycling then therapies should target cycling cells, whereas if cells are quiescent then therapies should either maintain dormancy or be toxic to dormant cells. Because this distinction is paramount to rational therapeutic development and administration, we investigated whether quiescence or balanced proliferation is the most likely etiology underlying metastatic dormancy. We recently published a computer simulation study that determined that balanced proliferation is not the likely driving force and that quiescence most likely participates in metastatic dormancy. As such, a greater emphasis on developing diagnostics and therapeutics for quiescent carcinomas is needed.

Figure 1

Probability of dormancy from in silico simulation. Dormancy is defined by a metastasis achieving 1,218 cycles while having a cell number greater than zero and below 1 million. The simulated balanced proliferation yields a dormant phenotype for patients harboring 1000 cryptic micrometases only between 49.7 – 50.8 percent survival probability regardless of starting cell number in the micrometasasis. Panel A shows the absolute number of dormant metastases at the end of the 1,218 cycles for a starting number of 2 cells per micrometastasis. Panel B depicts the metastatic fate for each of the survival probabilities demonstrating that same dormancy window (in red). The green area demonstrates that the majority of metastases die out even at survival probabilities approaching 60 percent. Metastases that become clinically evident (exceed 1 million cells) are shown in purple. From (13).

Figure 2

Schematic of an approach to study metastatic dormancy. The development of microphysiological systems such as organotypic bioreactors allows for the examination of cellular events in metastatic seeding and entry into dormancy or continuous outgrowth for a multiweek period (43). Shown is a cartoon depicting the fate of the micrometastasis following from the host tissue being in a more physiological state (upper pathway) versus a stressed, inflammaned or fibrotic organ (lower pathway). The stressed pathway prohibits micrometastases from entering dormancy while supporting emergence into frank metastases.