Pancreatic cancer is an especially aggressive cancer with a
high mortality rate – only 6% of those affected survive beyond 5 years. It is also the fourth most common death from
cancer worldwide. Even under conditions
when it was supposedly caught early on, the adenocarcinoma was successfully resected
and the liver was deemed to be free of the presence of metastatic legions,
patients, nonetheless suffered from subsequent metastatic disease. The obvious conclusion from this observation
is that there are latent metastases that persist and that are only detectable microscopically.
Furthermore, these latent metastases were believed to
represent a balance between cancer cell growth and cancer cell death precipitated
by the participation of the immune system in countering this growth. More recent evidence has indicated, however,
that quiescent single disseminated cancer cells (DCCs) are involved. An explanation for this quiescence has been elusive:
although involvement of the immune system is suspected. Of course, the question remains that if the
immune system is involved why is it not able to eliminate these DCCs entirely.
Douglas T. Fearon and his colleagues from the John Hopkins
University School of Medicine studied the role of adaptive immunity in response
to DCCs using the mouse model. Both mice
and humans with pancreatic duct adenocarcinoma (PDA) show DCCs resident in
liver. in both cases, these cells
display unusual phenotypic characteristics – negative for cytokeratin (CK) 19
and major histocompatibility complex class I (MHCI).
According to the authors, “The absence of MHCI and the
occurrence of specific CD8+ T cells in the genetically engineered mouse model
of PDA, and possible in patients with PDA, suggested that DCCs may be selected
by an anticancer immune response during the metastatic process.” This rationale
is represented by the image below.
The lack of the expression of MHCI in DCCs is indicative of
Endoplasmic Reticulum (ER) stress. ER
stress occurs within cells in certain pathological conditions when there is an accumulation
of unfolded proteins. Many proteins vital
to cell viability are maintained in precise folded configurations. If the mechanism responsible for maintaining
proteins in the folded state is disrupted, this results in so-called ER
stress. In this model, quiescent DCCs
lacking the expression of MHCI elude destruction by the CD8+ T cells. These surviving DCCs can then grow out into
full blown metastases if the immune response is subsequently disrupted. In other words, it is the immune response
that selects for quiescent DCCs. To test
this hypothesis, the investigators used a mouse model that would allow them to
introduce immunogenic PDA cells into seeded mice livers that were pre-immunized
and contained only quiescent DCCs lacking MHC1 and CK19. Those recipients that were not pre-immunized developed
macro-metastases. As a result, a subpopulation of PDA with the
phenotypic characteristics of DCCs were found in vitro and those cells proved
to be the precursors of DCCs in vivo.
The authors of this study conclude that, “A PDA-specific
adaptive immune response selects DCCs, in which the ER stress response accounts
for both quiescence and resistance to immune elimination. Accordingly,
outgrowth of DCCs to macro-metastases requires not only relief from the cancer
cell–autonomous ER stress response, but also suppression of systemic immunity.
Thus, the ER stress response is a cell-autonomous reaction that enables DCCs to
escape immunity and establish latent metastases.”
This finding may prove important in developing more effect therapeutic
strategies for combating pancreatic cancer that currently has an unacceptably
high mortality rate.
No comments:
Post a Comment