Beckerle Lecture #1:  Understanding cancer from its beginnings

Key words and terms:

cancer, growth factor signaling, integrins, cell adhesion, Ras, oncogenes, extracellular matrix, focal adhesion, actin cytoskeleton

Lecture notes

Cancer is a disease that affects an extremely large number of people within the general population.  Some cancers can be prevented  (for example, through not smoking, limiting sun exposure, HPV vaccine).  Moreover, early detection of cancer via screening significantly improves our ability to treat the disease.

 

Healthy tissue has well-organized cells and controlled cell growth, both of which are disturbed in cancer.

Hallmarks of cancer:

Briefly described within the lecture:

  1. Insensitivity to anti-growth signals
  2. Self-sufficiency in growth signals
  3. Evading apoptosis (programmed cell death)

Not discussed in the lecture:

  1. Limitless replicative potential
  2. Tissue invasion and metastasis
  3. Sustained angiogenesis

 

Each human cell has 23 pairs of chromosomes, containing genetic material/DNA organized into approximately 30,000 genes, which direct all cellular behavior.  Alterations in genes, through either inherited or acquired damage, are the early changes that lead to cancer.

Examples of human cancer susceptibility genes

Colon cancer:  APC

Breast cancer: BRCA1/2

Melanoma: p16

 

A genetic understanding of cancer can better allow for screening, early intervention, tailored therapy, and/or prevention.  Molecular analysis of the activities of all 30,000 human genes (by a technique called microarray) indicates that different genes are turned on/off in different kinds of cancers, as well as within tumors of the same type.  Thus, cancer is NOT a single disease with a single treatment.

 

Example of a cellular circuit mutated in cancer: Growth factor signaling

Cancer cells can acquire self-sufficiency in growth signaling in many ways, including:

  1. Increased production of growth factors
  2. Altered growth factor receptor profile of activity
  3. Altered/activated downstream elements in the growth factor signaling pathway
  4. Influencing cofactors

 

Integrin Receptors: an example of a cofactor involved in growth factor signaling

Integrins are:

- transmembrane, heterodimeric receptors for extracellular matrix

- concentrated at specialized cell-substratum adhesion sites called focal adhesions

- a link between the extracellular matrix and the actin cytoskeleton

- bidirectional signaling receptor molecules

- modulators of cell migration, proliferation and survival

 

Importantly, integrin-dependent adhesion is required for normal growth factor response.  The crosstalk between integrin signaling and growth factor signaling can occur at many levels.  Through this crosstalk, agents that affect integrin function can impinge upon cell growth/proliferation. For example, an anti-integrin antibody can inhibit the proliferation of ovarian tumor cells.  Indeed, integrin inhibitors are in clinical trials for numerous cancer applications.

 

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