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
References:
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.
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