The Six Hallmarks of Cancer: Circa 2000

Although each cancer exhibits a unique set of behaviors and growth characteristics (its phenotype), cancers do share a group of common characteristics or "hallmarks".

In 2000, Hanahan and Weinberg published a landmark paper on the "Hallmarks of Cancer" in the prestigious journal Cell (D. Hanahan, & Weinberg, R. A. (2000) The Hallmarks of Cancer, Cell, Vol. 100, pp. 57-70.) This article summarized a quarter of a century of research that viewed cancer as "a disease involving the dynamic changes in the genome".

The authors describe how tumor progression proceeds via a process in which each genetic change confers a growth advantage to the cell. These genetic changes can be grouped into six "hallmarks", which drive a population of normal cells to become a cancer.

This picture has been widely reproduced and summarizes processes that are viewed as key to understanding all cancers.

D. Hanahan, & Weinberg, R.A. (2000) The Hallmarks of Cancer, Cell, Vol. 100, pp. 57-70.

 

Inside the Original Tumor: Four of the Six “Hallmarks”

Four of the six hallmarks of cancer occur inside the cell: We discussed the cell cycle earlier to provide the needed background of how normal cells work to help you understand the changes that occur in cancer cell biology.

• Self-sufficiency in growth signals - Describes the observation that tumor cells
  grow even when they are not getting a message to grow.


• Insensitivity to anti-growth signals - They do not pay attention to the stop signs, which means the cell ignores messages telling it to stop growing.


• Evading apoptosis - A cancer cell learns to evade apoptosis (normally programmed cell death), leading to the accumulation of damaged cells. It ignores the signals telling it that it is time to die.


• Limitless replicative potential - Most mammalian cells can replicate (make an exact copy of themselves). Virtually all malignant cancer cells gain an ability to maintain their telomeres (ends of the chromosome), conferring "limitless replicative potential" and eventually picking up more and more mutations.

Mutations in certain genes have been discovered that promote these four processes. There is no single mutation that is able to create all six hallmarks of cancer. It requires many different mutations that accumulate over time to cause cancer.

Drugs are being developed to try to reverse many of these disruptions in normal cell functioning. The problem is that because cancer cells are unstable, they mutate in ways to evade these drugs.

 

Outside The Original Tumor: The Final Two “Hallmarks”

Increasing research has been devoted to processes beyond the inside of the tumor. These processes have also been recognized to be key to the natural history of cancer:

• Sustained angiogenesis (creation of blood supply)

Since cancer cells cannot survive without nutrients or at distances of more than 100 microns (~diameter of a strand of human hair) from a blood supply, they must initiate the formation of new blood vessels to support their growth via the process of "sustained angiogenesis".

	Without an adequate blood supply to bring in needed nutrients, a tumor cannot continue to grow. Scientists have found that tumor cells send out signals that encourage the growth of new blood vessels surrounding the tumor.
Image courtesy of the National Cancer Institute

This process is called angiogenesis, and drugs directed at knocking out this process are called
anti-angiogenesis. Examples include Avastin and Irressa.

• Tissue invasion (to nearby tissue) & metastases (to distant organs)

Some primary tumor cells acquire the ability to undergo "invasion and metastasis" whereby they leave their original location and move into the surrounding tissue. They eventually travel to distant sites in the body, forming new colonies and secondary tumors. It is almost always this metastases, rather than the primary tumor, which causes ultimate death.

	The new metastatic colonies resemble cells from their site of origin and disrupt the functioning of the host organ. Metastatic breast cancer in the lungs is still breast cancer, not lung cancer.
Image courtesy of the National Cancer Institute

 

CISN Summary: Six Hallmarks - Circa 2000

Problems can occur inside the cell that lead to cancer

• Cell division errors


• Signaling errors (copy errors)

Problems can occur outside the cell that lead to cancer

• Increased angiogenesis enables tumors to gain the needed oxygen to survive.


• Tissue invasion allows cancer to move further into the body and sometimes
  leading to metastasis.