Dormancy and Cancer relapse: Two sides of the same coin?
Written by Shiviya Raina and Sukanya Chakraborty.
“A monster more insatiable than the guillotine: Cancer”. It has for many years, been one of the leading causes of deaths worldwide. In 2012, approximately 14 million people were diagnosed with cancer around the world, out of which over half of the people died. By 2030 it is expected to take away 13 million lives.
What exactly is cancer?
Cancer is not a disease but a whole family of diseases, characterized by the abnormal, uncontrollable growth of cells. A tumour refers to a growth in the body, while metastasis is the term used to describe the spreading of the cancer from the primary site to distant organs.
“When a plant goes to seed, it is carried in all directions, but they can only live and grow if they fall on congenial soil.”
This quote, given by Steven Paget, the father of Metastasis theory, explains the seed and soil hypothesis of metastasis. This theory draws a parallel between cancer cells as seeds and the secondary organs to which it metastasizes as the soil. This hypothesis is also the reasoning as to why different cancers metastasize to different organs, For example, why do prostate and breast cancer like to metastasize to the bone but stomach and colorectal cancer metastasize mainly to the liver?
So, to elaborate, cancer cells grow into a tumour (primary tumour growth), cause new blood vessels to grow (angiogenesis), undergo physical changes, called Epithelial to Mesenchymal transition, which confers motility to them, and invade through the extracellular matrix (invasion) and enter the bloodstream (intravasation). Circulating Tumour Cells (CTCs) must extravasate into a secondary site. Once there as a Disseminated Tumour Cell (DTC), they can grow into a metastatic tumour or go dormant.
Surgical removal of the primary tumour heals a proportion of patients but in many cases the cancer relapses. 62% of breast cancer deaths occur 5 years after the surgery of the primary tumour. This can be explained by CLINICAL DORMANCY which is the period when you cannot detect residual tumor cells even though they are still actually present.
From the graph above it can be observed that the primary tumor starts proliferating until it reaches a threshold value after which it can’t be clinically detected. Treatment is initiated, after which the tumor burden decreases drastically but in a lot of cases the tumor burden starts proliferating again and crosses the threshold, this may not happen for years. So, clinical dormancy is the period between two peaks in the graph where the tumor burden is clinically undetectable.
In 1952, the pathologist Rupert Willis, (who first coined the term dormant cancer cell) observed that the time for clinical relapse can vary between 5 and 30 years. His argument was supported by another pathology professor, Geoffrey Hadfield who also elaborated that if this interval exceeds 6 years, it can be concluded that the dormant cells are in a state of temporary mitotic arrest.
So, how can we come to this conclusion that dormancy is a plausible reason for cancer relapse? Evidence suggests that disseminated tumor cells have been found in the bone marrow of breast and prostate cancer patients even at the time of surgery implying that even complete removal of the primary tumour does not always prevent dissemination to some other site and subsequent relapse.
At the cellular level, dormancy is considered as a balance between proliferating and dying cells (apoptosis). This type of dormancy is called tumor mass dormancy in which there is no net increase in tumor mass so it remains undetected. The other type, cellular dormancy refers to cells that are growth arrested, not proliferating but can also not be called dead and this is the most accepted explanation for the long period of clinical dormancy.
But why are these cells actually dormant?
Research says that this could be either due to lack of pro proliferation/growth factors or presence of anti proliferative signals at the host organs. Another way to control dormancy is by autophagocytosis (degradation of unwanted cellular components).
As we know the dormant cells are clinically undetectable, none of the imaging technologies such as MRI, CT, PET scan or X-ray are capable of picking up such small populations of cells. Biopsies are also not feasible because the location and size of the tumor is unknown. For example, in the bone scan, as shown in Fig. 3, it is clearly visible that the patient has residual cancer but by this stage it has grown significantly. The most promising test, therefore, is a blood test because the residual cells are likely to be travelling somewhere in the blood. However, it is still not sufficient to determine the originating and host organ.
One of the possible strategies to tackle dormancy is to develop dormant cancer cell or cancer stem cell specific therapy, specifically targeting those cells which have self renewal potential and are likely to be the precursor to a metastasis.
In conclusion, it can be said that dormant cancer cells are difficult to study in the lab. Hence dormancy is still associated with ambiguity, sparking active research in this area. Cell line models are being used for such studies but for this you need millions of cells which you won’t obtain until they are proliferating .Animal models are an alternative but they come with their own disadvantages like cost, time and ethical factors.