Ever wonder why 5 percent (5%) of metastatic cancer the primary site is never found! There is some enlightenment on the subject and is the purpose of this discourse.
Here are some well-known fact:
Experimental data from Ductal Carcinoma In Situ (DCIS) suggest that after “curative” treatment shows 2 -3% of cases will develop metastasis in spite of no residual primary. This is indeed the launch-pad for the inquiry.
We know that cancer cells have single or multiple constraints, which prevent them from progressing. The most important of these constraints is the Tumor suppressor genes. An example of that is the BRCA1. A mutation in that gene (disabling the function of the gene) leads to a higher risk of developing breast cancer. Consider the tumor suppressor gene as brakes in a car. Juxtaposed to the brake is the accelerator; the oncogene. An oncogene when overexpressed (driver with a lead foot) within the cell leads to cancer formation and promotion. An example of the oncogene would be HER 2-neu (erbB-2) in breast and stomach cancer. And MYC gene in lymphomagenesis.
Now researchers have tied the two processes together to come up with a composite concept in breast cancer-genesis.
The proposal based on experimental data suggests both the brake and acceleration process sequentially can go awry leading to the formation of the breast cancer cell. The tumor suppressor gene proposed in this experimental data is p38 gene (P38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases (MAPKs) that are responsive to stress stimuli, such as ultraviolet and irradiation, heat shock, and osmotic shock, and are involved in cell differentiation, apoptosis and autophagy. -Wikipedia), while HER 2-neu is the promoter oncogene. The latter leads to the initiation of the Epithelial Mesenchymal Transition (EMT). It is here that the transformed cell “by melting down of the barriers and cross talk between the EP tissues” causes the transition of the breast cancer cell into distant organs. Additionally, the Progesterone Receptors play a big role in allowing mammary cells to move through the mammary gland, hollow out a tubular and the branching network of milk ducts, where the cancer cell develops. These cancer cells, migrate through tissues and via blood vessels to distant organs (liver, bones, lungs etc.) still in their G0/G1 phase and can sit around until further stimuli (stressors: hormones, smoking, drinking, diet etc.) appear, which cause them to go forth and multiply (metastasis) (2).
If the p38 is turned off and the HER 2-neu is constantly turned on (no brake, only accelerator) one can conceptualize a progressive proliferation of the mammary cell turned cancerous forming a nidus to spread via the EMT into other tissues, lymphatic spaces and blood vessels. The Klein group showed in mice that 80% of metastasis originated from the early spread cells and not from the large tumors and the mechanism of spread was more efficient in early lesions than in large tumors (1).
Inherent in this experimental data is the suggestion that not only size of the primary tumor (where a growing primary tumor is known to cause spread to the adjacent lymphatics and lymph-nodes in a somewhat linear fashion – as most text books equate size equals the potential of stage of the disease) but also the molecular changes within the cancer cell have a part to play both in growth and spread. Hence the cases where metastases are noted first and then through elaborate histological/immunological/molecular diagnostics the primary source of the cancer is determined, are the very seeds of oncogeny.
The benefit of this understanding is both a study in ontogeny and oncogeny of the breast cell. The tautological basis of the experimental data is self-evident. From these basic science experiments, will come the genesis of better management of cancer. Determining the presence via impregnated none discs and nanowires to launch an investigation into potential sites where these wayward cells hide and molecularly targeting them to end them.
Notwithstanding the lead time bias issues, the logic here also explains the fallacy in the “time to spread” argument. It is suggested that 2/3rd of the life history of the cancer is already lived when the diagnosis is made in most cases. It is suggested in these experiments, the growth from 1 million cells (barely visible or causing signs and symptoms) to 1 billion cells (obvious tumors visible on radiological diagnostic tests), where most analyses are undertaken, time in the growth question does not appear to be a linear process and may also be dependent on molecular/hormonal/other stressor issues than believed.
Understanding reality is All.
“It was the lark, the herald of the morn,
No nightingale. Look, love, what envious streaks
Do lace the severing clouds in yonder east.
Night’s candles are burnt out, and jocund day
Stands tiptoe on the misty mountain tops.” - Shakespeare
Christoph A. Klein. Early dissemination seeds metastasis in breast cancer. Nature, 2016.
Julio A. Aguirre-Ghiso. Mechanism of early dissemination and metastasis in Her2 mammary cancer. Nature, 2016.