A scanning electron micrograph of a natural killer cell, part of the body’s innate immune system, facing off against a larger cancer cell.Chromosomes and cancerOne of the great, enduring scientific mysteries of cancer is the relationship between the disease and the body’s immune system. To what degree does the latter impact the former? Why doesn’t the immune system always stop cancer in its tracks?In today’s issue of Science, Maurizio Zanetti, MD, professor of medicine and director of the Laboratory of Immunology at the UC San Diego Moores Cancer Center, and colleague Navin R. Mahadevan discuss new findings that may help answer these questions, and perhaps lead to novel treatments that  specifically harness immune cells to fight and kill cancer cells.We asked Zanetti to elaborate:“For more than four decades, people have debated a hypothesis proposed by Australian immunologist and Nobel laureate Frank Macfarlane Burnet. Called the ‘cancer immune surveillance hypothesis,’ it suggests immune system cells recognize new or over-expressed moieties (portions) at the surface of aberrant cancer cells and eventually eliminate them. This hypothesis stirred much debate, met with conceptual and experimental hurdles and has had few true followers over the years. New work published in Science by a French research team led by Guido Kroemer suggests that cancer cells with an abnormal number of chromosomes serve as the trigger that can initiate immune surveillance.Diploid human cells contain 46 chromosomes, consisting of 44 autosomes and two sex chromosomes.  When eukaryotic cells divide, they distribute their genetic material equally and exactly to daughter cells through the process of mitosis. Ploidy (from the Greek word meaning “fold”) refers to the set of chromosomes. Cells with a normal set of chromosomes are said to be euploid (“good” fold) while cells that carry an abnormal number of a particular chromosome are aneuploid (“not a good” fold). Those cells that carry extra complete chromosome sets are polyploid/hyperploid or “many-fold.” Aneuploidy is common in cancer cells and may underlie their “immortal” growth. Polyploidy is fairly common in crop plants such as wheat, coffee, potatoes and cotton, but relatively rare in humans. The new study shows that cancer cells that are hyperploid trigger an anti-tumor immune response involving a complex biochemical cascade known as the endoplasmic reticulum (ER) stress response/unfolded protein response. The ER is an organelle that serves as the initial checkpoint in the biosynthesis, folding, assembly, and modification of membrane-bound and secreted proteins in mammalian cells.  This adaptive mechanism is a sort of internal rheostat upon which the decision is made as to whether cells experiencing stress should pause, return to homeostasis and survive, or die if the stress stimulus is too intense or protracted. (Zanetti and colleagues published a paper on how cancer cells exploit the ER stress response last year.) Among the biochemical sensors involved in this process is PERK (protein kinase RNA-like endoplasmic reticulum kinase), which under normal circumstances regulates the production of proteins from ribonucleic acid,  hence serving as buffer of excessive protein load. PERK has been shown to promote tumor cell adaptation and neovascularization in response to low content of oxygen (a condition quite frequent in tumor masses), but it is also implicated in the genesis of Diabetes mellitus, and in the regulation of hepatic steatosis, leading to nonalcoholic fatty liver disease, currently a global issue affecting both adults and children.  Our analysis provides new interpretative insights on the study and also points to new possibilities for therapeutic intervention in cancer patients that resist chemotherapy. For instance, cancer cells resistant to common chemotherapeutic agents, although hallmarked by an active PERK-mediated ER stress response/unfolded protein response, unexpectedly fail to engage the immune system and provoke immune control of cancer growth.This fact has led us to suggest that the molecules that selectively interfere with the activity of this biochemical sensor could be considered as a second line of treatment for tumors resistant to neoadjuvant chemotherapy. Consistent with this idea, a new study by my lab shows that breast cancer cells resistant to standard treatment re-acquire a malignant phenotype when subject to activation of the ER stress response/unfolded protein response. Additionally, we note an interesting extension of the Kroemer lab’s work, which implies that the ER stress response/unfolded protein response may be able to modify the repertoire of the moieties presented to the immune system, which ultimately dictates whether the immune system can control tumor growth. This suggests that by modulating the ER stress response/unfolded protein response in tumor cells, one may not only regulate their intrinsic ability to grow, but may also make them more sensitive to attack by the immune system.”

A scanning electron micrograph of a natural killer cell, part of the body’s innate immune system, facing off against a larger cancer cell.

Chromosomes and cancer

One of the great, enduring scientific mysteries of cancer is the relationship between the disease and the body’s immune system. To what degree does the latter impact the former? Why doesn’t the immune system always stop cancer in its tracks?

In today’s issue of Science, Maurizio Zanetti, MD, professor of medicine and director of the Laboratory of Immunology at the UC San Diego Moores Cancer Center, and colleague Navin R. Mahadevan discuss new findings that may help answer these questions, and perhaps lead to novel treatments that  specifically harness immune cells to fight and kill cancer cells.

We asked Zanetti to elaborate:

“For more than four decades, people have debated a hypothesis proposed by Australian immunologist and Nobel laureate Frank Macfarlane Burnet. Called the ‘cancer immune surveillance hypothesis,’ it suggests immune system cells recognize new or over-expressed moieties (portions) at the surface of aberrant cancer cells and eventually eliminate them.

This hypothesis stirred much debate, met with conceptual and experimental hurdles and has had few true followers over the years. New work published in Science by a French research team led by Guido Kroemer suggests that cancer cells with an abnormal number of chromosomes serve as the trigger that can initiate immune surveillance.

Diploid human cells contain 46 chromosomes, consisting of 44 autosomes and two sex chromosomes.  When eukaryotic cells divide, they distribute their genetic material equally and exactly to daughter cells through the process of mitosis. Ploidy (from the Greek word meaning “fold”) refers to the set of chromosomes. Cells with a normal set of chromosomes are said to be euploid (“good” fold) while cells that carry an abnormal number of a particular chromosome are aneuploid (“not a good” fold). Those cells that carry extra complete chromosome sets are polyploid/hyperploid or “many-fold.” Aneuploidy is common in cancer cells and may underlie their “immortal” growth. Polyploidy is fairly common in crop plants such as wheat, coffee, potatoes and cotton, but relatively rare in humans.

The new study shows that cancer cells that are hyperploid trigger an anti-tumor immune response involving a complex biochemical cascade known as the endoplasmic reticulum (ER) stress response/unfolded protein response. The ER is an organelle that serves as the initial checkpoint in the biosynthesis, folding, assembly, and modification of membrane-bound and secreted proteins in mammalian cells.  This adaptive mechanism is a sort of internal rheostat upon which the decision is made as to whether cells experiencing stress should pause, return to homeostasis and survive, or die if the stress stimulus is too intense or protracted. (Zanetti and colleagues published a paper on how cancer cells exploit the ER stress response last year.)

Among the biochemical sensors involved in this process is PERK (protein kinase RNA-like endoplasmic reticulum kinase), which under normal circumstances regulates the production of proteins from ribonucleic acid,  hence serving as buffer of excessive protein load. PERK has been shown to promote tumor cell adaptation and neovascularization in response to low content of oxygen (a condition quite frequent in tumor masses), but it is also implicated in the genesis of Diabetes mellitus, and in the regulation of hepatic steatosis, leading to nonalcoholic fatty liver disease, currently a global issue affecting both adults and children. 

Our analysis provides new interpretative insights on the study and also points to new possibilities for therapeutic intervention in cancer patients that resist chemotherapy. For instance, cancer cells resistant to common chemotherapeutic agents, although hallmarked by an active PERK-mediated ER stress response/unfolded protein response, unexpectedly fail to engage the immune system and provoke immune control of cancer growth.

This fact has led us to suggest that the molecules that selectively interfere with the activity of this biochemical sensor could be considered as a second line of treatment for tumors resistant to neoadjuvant chemotherapy. Consistent with this idea, a new study by my lab shows that breast cancer cells resistant to standard treatment re-acquire a malignant phenotype when subject to activation of the ER stress response/unfolded protein response.

Additionally, we note an interesting extension of the Kroemer lab’s work, which implies that the ER stress response/unfolded protein response may be able to modify the repertoire of the moieties presented to the immune system, which ultimately dictates whether the immune system can control tumor growth. This suggests that by modulating the ER stress response/unfolded protein response in tumor cells, one may not only regulate their intrinsic ability to grow, but may also make them more sensitive to attack by the immune system.”

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