We have recently written a Report on Cancer Associated Fibroblasts which considers a recent Consensus Report. Cancer is much more complex than initially thought. Originally
cancer was viewed in the context of the aberrant cell from a specific organ.
Namely a cell from an organ had a genetic alteration and the result was
aberrant proliferation and loss of function. Not only is a cell genetically
changed to promote its aberrant growth but the cell apparently participates
with its local environment to facilitate the process as well as developing a
shield to prevent attack by the immune system or other entities. In a sense, the
malignant cells manage to turn the very cells that
protect the body, against the body they are to protect. Thus, the cancer is an
amalgam of the aberrant cell and the collection of cells and entities about it
that enable the malignant cells to not only survive but to become an entity
unto itself. The implications are that any attempt to attack the cell alone may
be thwarted by the other entities which are not only enablers but protectors.
In contrast, one can think of wound healing. In certain
primitive animals we know that if you tale then, slice them mid body, head and
tail, and then allow them to regrow, the net result is two identical regrown
entities. There is no scar tissue, just a total regeneration of the original
entity. As one goes up the chain in developed animals the ability to regenerate
disappears and one is at best left with scar tissues. For the most part the
scar tissue is developed by fibroblasts.
Thus, if one were to consider a set of malignant cells as an injury then the application of the
fibroblasts and the formation of a putative scar may be a reasonable analogy. However,
in this case the "scar" is a mutually self-sustaining entity which
facilitates tumor growth and progression.
In this Note we examine some of the recent work regarding
Fibroblasts and their association with malignancies. In a recent Consensus
Statement, the authors have discussed
the ability to gain an understanding of cancer associated fibroblasts. As Sahai
et al note[1]:
Cancer-associated fibroblasts
(CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix
deposition and remodelling, extensive reciprocal signalling interactions with
cancer cells and crosstalk with infiltrating leukocytes. As such, they are a
potential target for optimizing therapeutic strategies against cancer. However,
many challenges are present in ongoing attempts to modulate CAFs for
therapeutic benefit. These include limitations in our understanding of the
origin of CAFs and heterogeneity in CAF function, with it being desirable to
retain some antitumorigenic functions.
This note is a focus on CAFs as well as other elements of
the tumor micro environment. The above remarks from the recent Consensus
Statement highlights another set of targets for the treatment of cancers. We
have experienced an explosion of ways to target the cancer cell itself. However
we know time and again that for a majority of the patients the response is
lacking. We address that issue herein where we argue that the TME and its
associated cells are the next barrier to breach.
Let us begin with the overall stroma, or in Greek, στρομα (packing bed, sack, bedding). The
stroma is the collection of elements that surround and support a cell. In
cancer cells the stroma can in a sense be identified as the extracellular
matrix, plus the cells supporting this such as fibroblasts.
As Maddaluno et al note in their review of fibroblast growth factors, "FGF", they note[2]:
Tissue injury initiates a complex repair process, which
in some organisms can lead to the complete regeneration of a tissue. In
mammals, However, the repair of most
organs is imperfect and results in scar formation. Both regeneration and repair
are orchestrated by a highly coordinated interplay of different growth factors
and cytokines. Among the key players are the fibroblast growth factors (FGFs), which control the
migration, proliferation, differentiation and survival of different cell types.
In addition, FGFs influence the expression of other factors involved in the regenerative
response. Here, we summarize current knowledge on the roles of endogenous FGFs
in regeneration and repair in different organisms and in different tissues and
organs. Gaining a better understanding of these FGF activities is important for appropriate
modulation of FGF signaling after injury to prevent impaired healing and to
promote organ regeneration in humans.
Thus, FGF in one sense are important in understanding the
regrowth of cells injured and also in turn their use in the explosive growth of
tumor cells. Cancer cells have a somewhat unique capability in engaging the
resources of a multiplicity of other cells, often one which would normally be
protective against invaders, and using these cells to assist in its own
proliferation. The amalgam of these cells is called the tumor micro
environment, TME.
The TME is often overlooked in histological studies where
the focus is on the morphology of the aberrant source cells. For example, in
examining a thyroid malignancy, one all too often examines the nucleus and
nucleolus of the originating thyroid cells. and is the growth of macrophages or
fibroblasts which have become an integral part of the malignancy. The same is
somewhat true of melanomas and prostate cancers and a wealth of other solid
malignancies.
As Biffi and Tuveson have noted[3]:
Stromal cells constitute the tumor microenvironment (TME), a niche where
neoplastic cells reside and progress. While the genetic and epigenetic drivers
of cancer cells have been extensively investigated, the mechanisms governing
the recruitment and activation of a major stromal cell type, cancer-associated fibroblasts
(CAFs), are largely unknown.
Investigating the origin and developmental lineage of
CAFs is essential for determining their functions and designing means to impede
their tumor-supportive roles.
CAFs may be globally viewed as the chief architects of
the TME due to their multiple functions. Indeed, they
are considered the major source of extracellular matrix components that alter physical-chemical
properties, concomitantly impairing vascular function and, therefore, drug
delivery.
Furthermore, CAFs secrete paracrine ligands that promote
tumor growth, angiogenesis and drug resistance, and
directly blunt T cell cytotoxicity while recruiting
immunosuppressive populations. Therefore, a multitude of
preclinical and clinical studies have attempted to antagonize CAFs as a
treatment modality for cancer.
However, the classical view of uniformly pro-tumorigenic
CAFs has been modified by the recent identification of subsets with tumor-suppressive
properties. This new appreciation that CAFs are a heterogenous population in
the TME prompts a reevaluation of CAF identities and
functions in efforts to develop more effective therapies.
We can make two basic observations. The first will be the
interactions with the cancer cell and the other elements of the tumor micro
environment, TME. We show this below:
The above is a simple demonstrative that shows that the
cancer cell can control and be controlled by a significant selection of the
TME.
In a similar fashion we can look at the CAF and see how it
influences the immune environment. This is a critical observation. We show this
below:
What is critical to note is that the CAF can control a large
set of the immune system. This in effect tends then to block any immunotherapeutic
approach to mitigating the cancer cells.
The previous section details some of the key points we will
discuss. The driver herein is the Consensus Statement recently issued and
referred to herein regarding CAFs. We will present the following:
1. Fibroblasts and FGF. These are the current cells and the
growth factors associated somewhat with them. FGF are a large group and a few
are fibroblast related whereas the name encompasses a larger
set of cells.
2. The ECM and TME: The ECM is the mass of extracellular
proteins and the tumor micro environment is the collection of other cells which
make up the total tumor mass.
3. Adipocytes: This will be a discussion on another set of
cells which are frequently forgotten, The often play a key role in the
malignant process.
4. ECM signalling discusses how the TME uses the ECM for
intercellular signalling of a holistically defined tumor mass.
5. There is a detailed discussion of the current
understanding of the CAF
6. The immune elements are discussed and a specific focus on
immunotherapeutic issues.
7. We then consider a specific malignancy, prostate cancer, and the issues of CAF.
Overall, understanding the TME and the elements that make it
up is critical to understand the "system" that functions in many
cancers. Hematopoietic cancers may be different in that they present themselves
bare of any significant TME. On the otherhand somatic cancers often have
developed a significant protective environment to sustain themselves.
Fundamentally, we must understand cancers as a set of
complex interacting systems. Instead of just targeting one aberrant element of
another we must target the system as a whole. Yet to do that we must first truly
understand the system. Our goal in the Note is to start with a step in that
process.
[1] Sahai
et al, A framework for advancing our understanding of cancer-associated
fibroblasts, Nature Reviews, Cancer, March 2020, Volume 20
[2] Maddaluno,
Fibroblast growth factors: key players in regeneration and tissue repair,
Development (2017) 144, 4047-4060
[3] Biffi
and Tuveson, Deciphering cancer fibroblasts, J. Exp. Med. 2018 Vol. 215 No.
12 2967–2968
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