The following message was updated on 10/21/2019 1:08:47 PM.
|Msg 30771 of 31962 at 10/21/2019 1:05:22 PM by
Those new to Manocept Science. The future is slow to advance but if/when RA approved..if KS trials succeed .." The view of metastasis as a macrophage metabolic disease can provide novel insight for therapeutic management."
Published in final edited form as:
On the Origin of Cancer Metastasis
The publisher's final edited version of this article is available at Crit Rev Oncog
See other articles in PMC that cite
the published article.
involves the spread of cancer cells from the primary tumor to
surrounding tissues and to distant organs and is the primary cause of
cancer morbidity and mortality. In order to complete the metastatic
cascade, cancer cells must detach from the primary tumor, intravasate
into the circulatory and lymphatic systems, evade immune attack,
extravasate at distant capillary beds, and invade and proliferate in
distant organs. Currently, several hypotheses have been advanced to
explain the origin of cancer metastasis. These involve an epithelial
mesenchymal transition, an accumulation of mutations in stem cells, a
macrophage facilitation process, and a macrophage origin involving
either transformation or fusion hybridization with neoplastic cells.
Many of the properties of metastatic cancer cells are also seen in
normal macrophages. A macrophage origin of metastasis can also explain
the long-standing “seed and soil” hypothesis and the absence of
metastasis in plant cancers. The view of metastasis as a macrophage
metabolic disease can provide novel insight for therapeutic management.....
XI. MANAGING METASTATIC CANCERS
a metabolic disease, most if not all cancers can be managed by
targeting those fuels necessary for their proliferation and survival.
The goal is to first transition energy metabolism of all normal cells of
the body to ketone bodies, which tumor cells cannot effectively use for
energy.14 It is well documented that most tumor cells require glucose for energy through glycolysis.216-218 Glutamine is also a major metabolic fuel for many cells of the immune system including macrophages.181,219,220
We recently showed that the simultaneous targeting of glucose and
glutamine under calorie restriction could significantly reduce systemic
metastatic cancer in the VM-M2 mouse model.221,222
Indeed, targeting these fuels was more effective in blocking metastasis
than was using the well-known toxic chemotherapies methotrexate or
Once metastatic cancer becomes recognized as a metabolic disease, new
and less toxic solutions will emerge for effective management.14
XII. CONCLUDING REMARKS
transition from an epithelial cell to a mesenchymal cell is considered
an underlying characteristic of metastasis. However, it is improbable
that random mutations acquired through a Darwinian selection process
could account for all of the myeloid-cell behaviors necessary for the
completion of the metastatic cascade. As an alternative to a series of
gain-of-function mutations and clonal selection, we propose that the
metastatic mesenchymal phenotype arises initially from respiratory
damage in macrophages or in epithelial-macrophage fusion hybrids, which
is then followed by compensatory fermentation. This would produce the
metastatic lesion images seen on PET. Inflammation and radiation damage
enhances hybridization while also damaging mitochondrial function over
time. It is our opinion that the myeloid origin of metastasis is the
most compelling explanation for the origin of metastasis and tumor
progression.14 We anticipate major advances in management of metastatic cancer once this explanation becomes more widely recognized."