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Cancer Pathophysiology - Intracellular Effects

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Cancer Pathophysiology - Intracellular Effects

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Cancer Pathophysiology: Intracellular Effects

5 characteristics of cancer cells that we cover in this tutorial:

  1. Cancer cells are self-sufficient; that is, they can grow in the absence of external growth signals.
  2. Cancer cells are insensitive to growth inhibitors; recall that growth and reproduction of non-cancer cells is regulated by signals that stall the cell cycle, for example.
  3. Cancer cells evade apoptosis, which otherwise occurs in response to irreparable DNA damage.
  4. Cancer cells are "immortal"; that is, they can continue replication long after their non-cancer counterparts experience mitotic cell death.
  5. Cancer cells exhibit altered cellular metabolism.

Genomic instability enables the cancer cell to adopt these defining characteristics.

To see an overview of the 8 Hallmarks, click here

Self-sufficiency

Growth factors

Cancer cells can synthesize their own growth factors.

For example, glioblastomas are characterized by synthesis of platelet-derived growth factor (PDGF).

To illustrate, we indicate a PDGF tyrosine kinase receptor traversing the cell membrane; we show that the cancer cell produces PDGF, which, in turn, interacts with its own receptor.

This is an example of a growth factor autocrine loop that promotes cell proliferation and transformation.

Transforming Growth Factor (TGF) is another example of a growth factor that engages in cancer cell autocrine loops.

RTKs

Overexpression of receptor tyrosine kinases (RTKs) can lead to breast cancer, for example, when gene amplification occurs.

To illustrate, we show overexpression of the Human Epidermal Growth Factor Receptor 2 (HER2), which causes increased cellular proliferation in approximately 15-30% of breast cancers.

Lung adenocarcinoma is also often associated with overexpression receptor tyrosine kinase.

Downstream of RTKs

Over-activation of downstream components of RTK's are implicated in approximately 15% - 20% cancers.

Examples include many lung and pancreatic adenocarcinomas, which are caused by mutations in the RAS gene family.

To illustrate an example of a RAS mutation, we draw a receptor tyrosine kinase in the cell membrane.

We show the membrane-associated RAS protein, and that it switches on and off: on, when GTP is bound; off, when GDP is bound.

Ordinarily, GTPase-activating proteins (GAPs) prevent constant activation by promoting GTP removal. However, in some cancers, RAS point mutations reduce GTPase activity, thus facilitating continuous RAS activation and cell proliferation.

Non-RTKs

Dysfunctional non-receptor tyrosine kinases can promote cancer.
For example, chronic myelogenous leukemia is associated with over-activation of the ABL non-receptor tyrosine kinase; this condition is caused by translocation and subsequent gene fusion.

To illustrate this, we move to the nucleus portion of our diagram, and show chromosome 9 with the abl gene; it codes for the ABL non-receptor tyrosine kinase, which is involved in cell proliferation, differentiation, migration, and death.

We then show chromosome 22 with the bcr gene.
Reciprocal translocation produces a shortened chromosome 22, aka, the Philadelphia chromosome, which now holds the brc-abl fusion gene. This new association amplifies the abl gene.

Dysregulation of transcription factors

Dysregulation of transcription factors is another mechanism to achieve self-sufficiency.
An example of this occurs in Burkitt lymphoma, which is caused by translocation and subsequent amplification of the MYC proto-oncogene. Normally, MYC transcription factors are tightly regulated because they are involved in multiple growth signaling pathways.

We return to the nucleus to show the initiating translocation:The c-myc proto-oncogene is on chromosome 8; an immunoglobulin gene locus is on chromosome 14.

Translocation rearranges these genes so that the c-myc gene is in close association with the immunoglobulin gene, resulting in MYC transcription factor amplification.

Cell cycle

Mutations can promote progression through the cell cycle, especially from the G1 to S phase, thus increasing the rate of replication.

For example, upregulation of CDK4 and D cyclins (often due to MYC oncogenes) is particularly effective at hastening the rate of the cell cycle.

Insensitivity to growth inhibitors

Promotes movement through the cell cycle.

Examples include loss-of-function in tumor suppressor genes for p16, Rb, and p53; without these critical components, cancer cells bypass the cell cycle checkpoints that ordinarily provide to respond to DNA damage.

Other examples of insensitivity include loss of function in TGF-beta receptors in several cancers, PTEN (phosphage and tensin homologue) in skin tumors, and APC (adenomatous polyposis coli) in colon cancer.

Evasion of apoptosis

Achieved via down regulation of pro-apoptotic factors (such as P53 or PTEN), or, via upregulation of anti-apoptotic factors.

For example, chronic lymphoblastic leukemia is caused by overexpression of the anti-apoptotic BCL2 protein, which is an integral protein of the mitochondrial membrane; we can see how this is adaptive in healthy cells, but, when overexpressed in damaged cells, allows proliferation of dysfunctional physiology.

Immortality

Cancer cells take on immortality via expression of telomerase, stem cell creation due to MYC oncogenes, and other mechanisms.

Telomere extension extends a cancer cell's life:
Most normal somatic cells contain very little telomerase, which is an enzyme that maintains the telomeres at the ends of chromosomes. Normally, after several rounds of cell division, the telomeres naturally shorten in the absence of telomerase. At some point, the "exposed" ends of the chromosome are sensed: mitotic crisis ensues and cell death usually follows.

However, cancer cells express high levels of telomerase, so that with each round of cell division they maintain telomere length, thus achieving immortality.

Altered Cell Metabolism

Often referred to as the Warburg effect; is due to MYC oncogenes and other cellular abnormalities.

In the mitochondrion, cancer cells use aerobic glycolysis to fuel the biosynthesis of new cellular machinery. Thus, increased glucose and glutamine consumption are markers of cancer cells.

Interestingly, this altered cellular metabolism is also used by non-cancerous proliferating cells during development; thus, cancer cells are able to take advantage of and manipulate cellular machinery that is already present.

Full-Length Text

  • Here we will learn 5 key hallmarks of cancer pathophysiology that primarily affect the cancer cell, itself.
    • In Part II, we'll learn how cancer cells interact with the extracellular environment as they invade and metastasize.
  • To begin, list 5 characteristics of cancer cells that we'll cover in this tutorial:
    • Cancer cells are self-sufficient; that is, they can grow in the absence of external growth signals.
    • Cancer cells are insensitive to growth inhibitors; recall that growth and reproduction of non-cancer cells is regulated by signals that stall the cell cycle, for example.
    • Cancer cells evade apoptosis, which otherwise occurs in response to irreparable DNA damage.
    • Cancer cells are "immortal"; that is, they can continue replication long after their non-cancer counterparts experience mitotic cell death.
    • Cancer cells exhibit altered cellular metabolism.

As we move through this tutorial, bear in mind that genomic instability enables the cancer cell to adopt these defining characteristics.

  • To set up our diagram, draw a large cell; indicate the cytoplasm, nucleus, and a
    representative mitochondrion.
  • Now, let's show some examples of self-sufficiency mechanisms; we'll designate these as 1a through 1f.

We'll start in the cytoplasm with alterations to receptor tyrosine kinases.

  • So, first write cancer cells can synthesize their own growth factors.
    • For example, glioblastomas are characterized by synthesis of platelet-derived growth factor (PDGF);
  • To illustrate, indicate a PDGF tyrosine kinase receptor traversing the cell membrane; show that the cancer cell produces PDGF, which, in turn, interacts with its own receptor.
    • This is an example of a growth factor autocrine loop that promotes cell proliferation and transformation.
  • Write that Transforming Growth Factor (TGF) is another example of a growth factor that engages in cancer cell autocrine loops.
  • Next, write that overexpression of receptor tyrosine kinases (RTKs) can lead to breast cancer, for example, when gene amplification occurs.
  • To illustrate, show overexpression of the Human Epidermal Growth Factor Receptor 2 (HER2), which causes increased cellular proliferation in approximately 15-30% of breast cancers.
    • Lung adenocarcinoma is also often associated with overexpression receptor tyrosine kinase.
    • Over-activation of downstream components of RTK's are implicated in approximately 15% - 20% cancers; examples include many lung and pancreatic adenocarcinomas, which are caused by mutations in the RAS gene family.
  • To illustrate an example of a RAS mutation, draw a receptor tyrosine kinase in the cell membrane.
  • Then, indicate the membrane-associated RAS protein, and show that it switches on and off: on, when GTP is bound; off, when GDP is bound.
  • Ordinarily, GTPase-activating proteins (GAPs) prevent constant activation by promoting GTP removal.
    • However, in some cancers, RAS point mutations reduce GTPase activity, thus facilitating continuous RAS activation and cell proliferation.
  • Next, write that dysfunctional non-receptor tyrosine kinases can promote cancer.
    • For example, chronic myelogenous leukemia is associated with over-activation of the ABL non-receptor tyrosine kinase; this condition is caused by translocation and subsequent gene fusion.
  • To illustrate this, move to the nucleus portion of our diagram, and show chromosome 9 with the abl gene; write that it codes for the ABL non-receptor tyrosine kinase, which is involved in cell proliferation, differentiation, migration, and death.
  • Then, show chromosome 22 with the bcr gene.
  • Indicate that reciprocal translocation produces a shortened chromosome 22, aka, the Philadelphia chromosome, which now holds the brc-abl fusion gene.
    • This new association amplifies the abl gene.
  • Next, write that dysregulation of transcription factors is another mechanism to achieve self-sufficiency;
    • An example of this occurs in Burkitt lymphoma, which is caused by translocation and subsequent amplification of the MYC proto-oncogene.
    • Normally, MYC transcription factors are tightly regulated because they are involved in multiple growth signaling pathways.

Return to the nucleus to show the initiating translocation:

  • Show that the c-myc proto-oncogene is on chromosome 8; on chromosome 14, show an immunoglobulin gene locus.
  • Translocation rearranges these genes so that the c-myc gene is in close association with the immunoglobulin gene, resulting in MYC transcription factor amplification.
  • Lastly in the self-sufficiency category, indicate that mutations can promote progression through the cell cycle, especially from the G1 to S phase, thus increasing the rate of replication.
    • For example, upregulation of CDK4 and D cyclins (often due to MYC oncogenes) is particularly effective at hastening the rate of the cell cycle.
  • In a similar fashion, insensitivity to growth inhibitors promotes movement through the cell cycle.
  • Indicate that important examples include loss-of-function in tumor suppressor genes for p16, Rb, and p53; without these critical components, cancer cells bypass the cell cycle checkpoints that ordinarily provide to respond to DNA damage.
  • Write that other examples of insensitivity include loss of function in TGF-beta receptors in several cancers, PTEN (phosphage and tensin homologue) in skin tumors, and APC (adenomatous polyposis coli) in colon cancer.
  • Next, write that evasion of apoptosis and pathologic survival is achieved via down regulation of pro-apoptotic factors (such as P53 or PTEN), or, via upregulation of anti-apoptotic factors.
    • For example, indicate that chronic lymphoblastic leukemia is caused by overexpression of the anti-apoptotic BCL2 protein, which is an integral protein of the mitochondrial membrane; we can see how this is adaptive in healthy cells, but, when overexpressed in damaged cells, allows proliferation of dysfunctional physiology.
  • Next, write that cancer cells take on immortality via expression of telomerase, stem cell creation due to MYC oncogenes, and other mechanisms.

In our diagram, let's show how telomere extension extends a cancer cell's life.

  • First, indicate that most normal somatic cells contain very little telomerase, which is an enzyme that maintains the telomeres at the ends of chromosomes.
  • Show a chromosome, and indicate its telomeres; show that after several rounds of cell division, the telomeres naturally shorten.
    • At some point, the "exposed" ends of the chromosome are sensed: mitotic crisis ensues and cell death usually follows.
  • However, show that cancer cells express high levels of telomerase, so that with each round of cell division they maintain telomere length, thus achieving immortality.
  • Finally, write that the altered cellular metabolism of cancer cells, which is often referred to as the Warburg effect, is due to MYC oncogenes and other cellular abnormalities.
  • In the mitochondrion, indicate that cancer cells use aerobic glycolysis to fuel the biosynthesis of new cellular machinery.
    • Thus, increased glucose and glutamine consumption are markers of cancer cells.
  • Interestingly, this altered cellular metabolism is also used by non-cancerous proliferating cells during development.
    • Thus, cancer cells are able to take advantage of and manipulate cellular machinery that is already present.

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