|
The Tumor: a complex ecosystem
|
Tumor cells interact with the
cells of the host in which they appear and develop.
The reciprocal interactions occurring between
tumor cells and host cells influence
the progression of a tumor.
In addition, non-cellular components produced by host
cells and/or tumor
cells themselves influence tumor
cells properties.
Cancer cells have
been the focus of interest in cancer
research for many years.
However, carcinomas are not only composed of
tumor cells, but they also contain
vessels (blood and lymphatic vessels) and different cell types issued from the
host tissue. In addition, there is a non-cellular compartment consisting of
various soluble molecules (chemical messager between cells) and insoluble matrix
components forming an extracellular scaffold referred as extracellular matrix (ECM).
The classical view of cancer
focused on cancer
cells has for long ignored the
contribution of other cell types to the malignant phenotype. The concept that
factors of the tumor
microenvironment play an active role in the evolution of
a cancer and in particular
in the formation of metastasis exists for a long time.
This concept was however overshadowed by an almost exclusive focus of the
cancer
research community on the cancer
cell genome and on mutations leading to the
transformation of normal cells into malignant cells. This situation has recently changed.
The notion that the tumor
microenvironment plays a crucial role in
cancer development
and in its progression is now widely accepted among
cancer researchers.
|
|
The tumor compartment
|
Cancer is fundamentally a
disease of regulation of tissue growth. In order for a
normal cell to transform into a cancer
cell, genes which regulate cell growth and
differentiation must be altered. Genetic changes can occur at many levels, from
gain or loss of entire chromosomes to a mutation affecting a single DNA nucleotide.
Often, the multiple genetic changes which result in
cancer may take many years to
accumulate. During this time, the biological behavior of the pre-malignant cells
slowly change from the properties of normal cells to cancer-like properties. Among
the distinguishing traits are an increased number of dividing cells, variation in
nuclear size and shape, variation in cell size and shape, loss of specialized cell
features, and loss of normal tissue organization.
In a 2000 article by Hanahan and Weinberg, the biological properties of malignant
tumor
cells were summarized as follows:
Acquisition of self-sufficiency in growth signals, leading to unchecked growth.
Loss of sensitivity to anti-growth signals, also leading to unchecked growth.
Loss of capacity for apoptosis, in order to allow growth despite genetic errors and external anti-growth signals.
Loss of capacity for senescence, leading to limitless replicative potential (immortality)
Acquisition of sustained angiogenesis, allowing the tumor to grow beyond the limitations of passive nutrient diffusion.
Acquisition of ability to invade neighbouring tissues, the defining property of invasive carcinoma.
Acquisition of ability to build metastases at distant sites.
These biological changes are classical in carcinomas; other malignant
tumor may not need
all to achieve them all. In addition, not all the
cancer cells are dividing.
Rather, a subset of the cells in a
tumor, called
cancer stem cells,
replicate themselves and generate differentiated cells.
 |
 |
A tumor is now viewed as a complex dynamic and evolving ecosystem. |
|
|
The host cells of a tumor
|
 |
A fibroblast is a type of cell that synthesizes, deposits and maintains the extracellular
matrix of many tissues. Fibroblasts provide a structural framework (stroma) for many tissues,
and play a critical role in wound healing. In
cancer, fibroblasts
are often referred as
"active fibroblasts" or "myofibroblasts"". They contribute to the desmoplasic reaction
(desmoplasia) characterized by an excessive deposition of extracellular matrix components.
Myofibroblasts promote the growth of
cancer by producting
growth factors and extracellular
matrix components. Myofibroblasts are a key determinant in the malignant progression of
cancer and represent an
important target for cancer therapies.
|
 |
Endothelial cells are specialized cells forming the wall of blood or lymphatic vessels.
Normal cells depend on blood vessels to supply oxygen and nutrients but the vascular
architecture is more or less constant in adult. It is widely recognized that
tumors
required the recruitment of new blood vessels to grow beyond a certain size.
cancer cells induce
the activation of blood endothelia cells leading to the
formation of new blood vessels during a process referred as angiogenesis.
Blood vessels provide oxygen and nutrients needed for
tumor survival and expansion and,
in addition, they provide an access to the blood circulation in order
|
to disseminate into distant sites and form metastases. More recently, lymphangiogenesis,
the formation of new lymphatic vessels have emerged as an important step of the
metastatic dissemination into lymph node.
|
 |
Innate immune cells act as independent cells and are key actors of the innate immune system.
Innate immune defenses are non-specific, meaning these systems respond to pathogens or
abnormal (foreign) cells. This system does not confer long-lasting immunity.
The innate leukocytes (white blood cells) include the phagocytes (macrophages,
neutrophils, and dendritic cells), mast cells, eosinophils, basophils, and natural killer cells.
Macrophages are cells within the tissues that originate from specific white blood
cells called monocytes. Tumor-associated macrophages (TAM) represent a major
|
component of
tumor infiltrates.
High numbers of TAM have been observed in many
tumors. The extent of
the macrophage infiltrate correlates positively with angiogenesis and negatively with prognosis
in some cancer. Macrophages
may have both pro- and anti-tumor activities. TAMs can adopt a
trophic role for cancer
by facilitating angiogenesis, matrix breakdown and
tumor cell motility.
On the other hand, TAM can inhibit the angiogenesis by contributing to the generation of
inhibitors of angiogenesis.
Neutrophils or neutrophil granulocytes are the most abundant type of white blood
cells in humans and form an essential part of the immune system. They form part of the
polymorphonuclear cell family (PMN's) together with basophils and eosinophils. Neutrophils
are normally found in the blood stream. However, during the beginning (acute) phase of inflammation,
particularly as a result of bacterial infection, neutrophils migrate toward the site of inflammation.
Accumulating evidence also indicate their important role during
cancer progression.
Dendritic cells (DCs) are immune cells and form part of the mammalian immune system.
Their main function is to process antigen material and present it on the surface to other cells
of the immune system, thus functioning as antigen-presenting cells.
A mast cell (or mastocyte) is a resident cell of several types of tissues and contains
many granules rich in histamine and heparin. Mast cells are best known for their role in allergy.
They play an important protective role as well, being intimately involved in wound healing and
defense against pathogens. Mast cells have been shown to accumulate within and around the
tumors
of different origin. Their functions in
cancer remain controversial.
Natural killer cells (or NK cells) are a type of cytotoxic lymphocyte that constitute
a major component of the innate immune system. NK cells play a major role in the rejection of
tumors and cells infected by viruses.
The cells kill by releasing small cytoplasmic granules
of proteins called perforin and granzyme that cause the death of target cell.
The adaptive immune response is antigen-specific and requires the recognition of specific "non-self"
antigens during a process called antigen presentation. Antigen specificity allows for the generation
of responses that are tailored to specific pathogens, pathogen-infected cells or even
cancer cells.
Lymphocytes are special types of leukocytes contributing to the adaptive immune system.
B cells and T cells are the major types of lymphocytes.
cancer immunosurveillance is a
theory according which lymphocytes act as sentinels in recognising and eliminating continuously
arising, nascent transformed cells.
cancer immunosurveillance
appears to be an important
host protection process that inhibits carcinogenesis and maintains regular cellular homeostasis.
|
|
|
The non cellular compartment of a tumor
|
 |
The extracellular matrix (ECM) is an extracellular scaffold displaying multiple functions.
Extracellular matrix includes the interstitial matrix and the basement membrane. Interstitial
matrix is present between various cells (i.e., in the intercellular spaces). Gels of polysaccharides
and fibrous proteins fill the interstitial space and act as a compression buffer against the
stress placed on the ECM. Basement membranes are sheet-like depositions of ECM on which various
epithelial cells rest.
|
Due to its diverse nature and composition, the ECM can serve many functions, such as providing
support and anchorage for cells, segregating tissues from one another, and regulating intercellular
communication. The ECM regulates a cell's dynamic behaviour. In addition, it sequesters a wide range
of soluble cellular factors, and acts as a local depot for them.
|
 |
Soluble factors represent a large array of proteins including among others growth
factors, proteinases, proteinase inhibitors. Growth factors are important for regulating a
variety of cellular processes (proliferation, differentiation, apoptosis, angiogenesis...).
They typically act as signalling molecules between cells. Examples are cytokines and hormones
that bind to specific receptors on the surface of their target cells.
|
|
Proteinases are a diverse and important group of enzymes representing >2% of the human genome.
Proteinases are divided into four major groups according to the character of their catalytic
active site and conditions of action: serine proteinases, cysteine proteinases, aspartic
proteinases, and metalloproteinases. Proteinases activity is essential for the dynamic
regulation of cell functions and for modulating the cellular, tissue and systemic environments,
aberrations of which are associated with many diseases (at least 76 different hereditary diseases
are due to mutations in proteinase genes). Historically, proteinases were thought to function
mainly as enzymes that degrade structural components of the ECM. However, proteolysis can create
space for cells to migrate, can produce specific substrate-cleavage fragments with independent
biological activity, can regulate tissue architecture through effects on the ECM and intercellular
junctions, and can activate, deactivate or modify the activity of signalling molecules, both
directly and indirectly. Because cells have receptors (for example, integrins) for structural
ECM components, proteinases can also affect cellular functions by regulating the ECM proteins
with which the cells interact. Proteinases substrates include peptide growth factors, tyrosine
kinase receptors, cell-adhesion molecules, cytokines and chemokines, as well as other proteinases.
|
|
|
Morphological evidence of host involvement in cancer:
|
 |
(A) the desmoplastic reaction or desmoplasia consisting of the presence of numerous fibroblast-like cells and excessive deposit of extracellular matrix, |
 |
(B) the inflammation and immune response represented by the infiltration of inflammatory and immune cells, |
 |
(C) the angiogenesis evidenced by newly formed blood and lymph vessels. |
|
|
