Cancer Pathophysiology - Extracellular Effects

Sections

Overview
Primary tumor
Metastatic Cascade
Host Immune Evasion
Full-Length Text
References

Overview

This is Part II of Cancer Pathophysiology; here we will learn how cancer cells interact with the extracellular environment to ensure their growth and survival. In part I, we learned 5 key characteristics of cancer cells.

Angiogenesis provides the growing tumor with its own blood supply.

Invasion and metastasis is how cancer cells spread from primary to secondary and tertiary sites; this is the major cause of morbidity and death from cancer.

Evasion of host immune defenses allows the cancer cell to proliferate and spread.

To set up the diagram, we show two structural components of the extracellular matrix (ECM): the basement membrane and interstitial tissue, which comprise various proteins including collagen and fibronectin. We show a blood vessel, and label its basement membrane and inner layer of endothelial cells.

Be aware that cancer cells can enter the circulation via blood or lymphatic vessels, and that some cancers have proclivities for specific vessel types.

To see a review of all 8 Cancer Hallmarks, click here

Primary tumor

Cancer cells undergo clonal expansion and diversification to become a primary tumor.

When the cellular mass grows to more than approximately 2 cm, it requires its own blood supply; below this threshold, the cells are able to obtain nutrients via diffusion.

Angiogenesis: Hypoxemia induces the release of VEGF and other angiogenic molecules. As a result, new vessels sprout from the original vessel, but are different in key ways: they tend to be tortuous and leaky, and may even incorporate tumor cells into their walls.

Metastatic Cascade

The series of events that enables cells of a primary tumor to spread to new sites.

3 components: invasion of the ECM, intravasation (entry into the circulation) and extravasation (exiting the circulation).

Invasion often includes the epithelial-mesenchymal transition and migration through the ECM.
Only one or a few cells break away from the primary tumor at a time. This may be a self-selective process, in that only some tumor cells display the necessary plasticity.

Epithelial to mesenchymal transition involves the following:
Loosening of cell-to-cell adhesion; more specifically, downregulation of E-cadherins, which tightly hold epithelial cells to each other.

Recognize that loosening of intercellular connections increases the cancer cell's vulnerability and susceptibility to anoikis, which is a form of programmed cell death of anchorage-dependent cells. Thus, only cancer cells that are able to avoid this can participate in the metastatic cascade.

The dissociated cell takes on new morphology: it becomes spindle-shaped and acquires contractile abilities that enable motility.

The cell begins to secrete proteases and/or induces their release from surrounding stromal tissues to degrade the ECM.

As the ECM degrades, the cancer cell forms new attachments to ECM proteins, which facilitates its migration.
Macrophage chemokines guide the cell's movement towards the vasculature.

Intravasation is the process by which the cancer cell moves through the vessel wall; this, too, is guided by tumor-associated macrophages.

Once in the circulation, the cancer cells may attract T lymphocytes and platelets; it can activate coagulation factors and form an embolus.
This aggregation may protect the tumor cells from destruction by physical stressors, anoikis, or immune defenses.

Furthermore, emboli formation may promote implantation on the endothelial surface, which allows for extravasation of cancer cells.

Extravasation is similar to intravasation, but in reverse.
It tends to occur within the first capillary bed encountered by the embolus, but is also influenced by stromal characteristics, such as chemokine and adhesion molecule expression.
As the metastatic tumor grows, it, too, can flip the "angiogenic switch" to develop its own blood supply.

Host Immune Evasion

Cancer cells can downregulate expression of MHC proteins and tumor antigens, thus "hiding" from the immune system.

They can suppress immune activity of T cells, macrophages, and granulocytes. Some studies show that cancer cells can shift T cell development to favor the production of regulatory T cells.

Cancer cells can also release immunosuppressive cytokines, such as TGF-beta.

Chronic Inflammation & Cancer
– It appears that interactions between cancer cells and inflammatory cells may promote and sustain tumor growth.
– For example, inflammatory cells release growth factors and remove growth suppressors; as we saw earlier, macrophages release chemicals that guide cancer cells during invasion and metastasis, and can even suppress the immune system's response to cancer cells.

• Review Carcinogenesis

Full-Length Text

• This is Part II of Cancer Pathophysiology; here we will learn how cancer cells interact with the extracellular environment to ensure their growth and survival. In part I, we learned 5 key characteristics of cancer cells.

• To begin, indicate that we'll discuss angiogenesis, which provides the growing tumor with its own blood supply.
  • We'll learn about invasion and metastasis, which is how cancer cells spread from primary to secondary and tertiary sites; write that this is the major cause of morbidity and death from cancer;
    -And, we'll address mechanisms of cancer evasion of host immune defenses.

• To set up the diagram, show two structural components of the extracellular matrix (ECM): the basement membrane and interstitial tissue, which comprise various proteins including collagen and fibronectin.

• Indicate a blood vessel, and label its basement membrane and inner layer of endothelial cells.
  • Be aware that cancer cells can enter the circulation via blood or lymphatic vessels, and that some cancers have proclivities for specific vessel types.

• Now, draw a cancer cell; indicate that it undergoes clonal expansion and diversification to become a primary tumor.

• Show that when this cellular mass grows to more than approximately 2 cm, it requires its own blood supply; below this threshold, the cells are able to obtain nutrients via diffusion.

• To illustrate some key points regrading angiogenesis, create a smaller diagram:

• Draw an original host blood vessel passing by a tumor.

• Indicate that hypoxemia induces the release of VEGF and other angiogenic molecules.

• As a result, new vessels sprout from the original vessel, but are different in key ways: they tend to be tortuous and leaky, and may even incorporate tumor cells into their walls.

• Next, we'll show key events of the "metastatic cascade," which is the series of events that enables cells of a primary tumor to spread to new sites.

• First, indicate that we can divide this process into 3 components: invasion of the ECM, intravasation (entry into the circulation) and extravasation (exiting the circulation).

• Show that the first step, invasion, often includes the epithelial-mesenchymal transition and migration through the ECM.

Let's show this in more detail; as we do so, notice that only one or a few cells break away from the primary tumor at a time. This may be a self-selective process, in that only some tumor cells display the necessary plasticity.

• First, draw some cells of a primary tumor, and indicate that they are tightly adhered to one another.

• Nearby, show the basement membrane and extracellular matrix.

• Now, indicate that the epithelial to mesenchymal transition involves the following:
  • Loosening of cell-to-cell adhesion; more specifically, downregulation of E-cadherins, which tightly hold epithelial cells to each other, is downregulated.

• Recognize that loosening of intercellular connections increases the cancer cell's vulnerability and susceptibility to anoikis, which is a form of programmed cell death of anchorage-dependent cells.
  • Thus, only cancer cells that are able to avoid this can participate in the metastatic cascade.

• Next, show that the dissociated cell takes on new morphology: it more spindle-shaped and acquires contractile abilities that enable motility.

• Additionally, the cell begins to secrete proteases and/or induces their release from surrounding stromal tissues to degrade the ECM.

• As the ECM degrades, the cancer cell forms new attachments to ECM proteins, which facilitates its migration.

• Finally, show that macrophage chemokines guide the cell's movement towards the vasculature.

• Now, return to our main diagram, and show that intravasation is the process by which the cancer cell moves through vessel wall; this, too, is guided by tumor-associated macrophages.

• Once in the circulation, the cancer cells may attract T lymphocytes and platelets; furthermore, it can activate coagulation factors and form an embolus.
  • This aggregation may protect the tumor cells from destruction by physical stressors, anoikis, or immune defenses.

• Furthermore, emboli formation may promote implantation on the endothelial surface, which allows for extravasation of cancer cells.
  • Extravasation is similar to intravasation, but in reverse.
  • It tends to occur within the first capillary bed encountered by the embolus, but is also influenced by stromal characteristics, such as chemokine and adhesion molecule expression.

• Indicate that, as the metastatic tumor grows, it, too, can flip the "angiogenic switch" to develop its own blood supply.

Next, let's consider a few ways in which cancer cells evade the host immune defense:

• Draw a cancer cell, and indicate that it can downregulate expression of MHC proteins and tumor antigens, thus "hiding" itself from the immune system.

• Show that the cancer cell can suppress immune activity of T cells, macrophages, and granulocytes; furthermore, some studies show that cancer cells can shift T cell development to favor the production of regulatory T cells.

• Indicate that cancer cells can also release immunosuppressive cytokines, such as TGF-beta.

• Finally, consider the emerging relationship between chronic inflammation and cancer: it appears that interactions between cancer cells and inflammatory cells may promote and sustain tumor growth.

• For example, inflammatory cells release growth factors and remove growth suppressors; as we saw earlier, macrophages release chemicals that guide cancer cells during invasion and metastasis, and can even suppress the immune system's response to cancer cells.

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