Cancer often returns years after successful treatment, and it often metastasizes to new organs, which is known as latent metastasis. Certain cancer cells, recently labeled as latency competent cancer (LCC) cells, are capable of becoming dormant for extended periods of time, thereby evading the body’s immunity and leading to cancer recurrence in distant organs after the initial remission.
A new study by Srinivas Malladi, PhD, a researcher at Memorial Sloan Kettering Cancer Center (MSKCC), and colleagues,1 provides a new window into how latent metastasis occurs.
“Understanding latent metastasis is the biggest untapped opportunity to have a major impact on cancer. But so far, no one has been able to tackle it,” said Joan Massagué, PhD, Director of the Sloan Kettering Institute, and Head of Memorial Sloan Kettering’s Center for Metastasis Research, and coinvestigator of the study. She discussed the study results on MSKCC’s website (www.mskcc.org).
Tumors continually shed cells inside the host, and although most of these cells will die, a few survive and remain hidden, only to show up in a different part of the body at a later time, thus leading to latent metastasis in patients who are clinically considered disease-free after cancer treatment.
New Model Isolates LCC Cells
Researchers at MSKCC created a model that allowed them to isolate LCC cells from patients with early-stage lung or breast cancer. Patients with breast cancer or lung cancer have high rates of disease recurrence, with approximately 25% of patients with HER2-positive breast cancer and 50% of patients with lung cancer experiencing recurrence after surgery or after chemotherapy.
The isolated LCC cells were labeled with a fluorescent tag and were injected into mice. Most mice remained healthy for 3 months; however, LCC cells were recovered from the lungs and kidneys of some of the mice.
After detecting the LCC cells, the researchers were able to investigate how the cells remained hidden, noting that LCC cells act like stem cells by being able to divide, which allows them to travel to distant organs and generate late metastases. In addition, according to Dr Malladi, some LCC cells produce a protein called WNT inhibitor that blocks cell division.
This forces cells into suspended animation, which slows their growth, allowing the cell to hide and survive in the body undetected by the immune cells, or the natural killer (NK) cells. Although the job of the NK cells is to kill cancer cells, nondividing LCC cells are ignored by the NK cells, because they do not produce the molecules that NK cells detect. Most chemotherapies also only kill dividing cells, again allowing the LCC cells to avoid detection and remain in the body undetected for a long time.
According to Dr Malladi and colleagues, this explains why although most LCC cells are killed, a few remain in the body undetected. The cells may mutate over time, further allowing them to avoid detection by the immune system.
The relationship between latent mutations and the immune system remains unknown, but this new research helps to explain the interaction between LCC cells and immune cells. As a result, new treatment options—such as prodding LCC cells to produce molecules that would then be detected by NK cells—can be explored.
“People have known for years that latent metastasis exists, but there has been no good way to study it,” said Dr Malladi.
Now that Dr Massagué and his team have a better idea of how LCC cells avoid detection, they hope to work with immunologists to further explore these cells, which they hope will eventually lead to new immunotherapies.
Reference
- Malladi S, Macalinao DG, Jin X, et al. Metastatic latency and immune invasion through autocrine inhibition of WNT. Cell. 2016;165:45-60.