PTEN, TSC2, and tumorigenesis

July 18, 2005

Two papers in the August 1 issue of Genes & Development explore the genetic interactions between two well-known tumor suppressor proteins, PTEN and TSC2.

Together, the studies shed new light on the long-standing question as to how the loss of either protein (which act in the same pathway to inhibit mTOR signaling and cell growth) can have such dramatically different effects on tumor physiology. While PTEN mutations underlie the cancer predisposition syndrome, Cowden disease, and are common to many types of human cancers (including prostate), the development of malignancy in TSC patients is quite rare. Though performed independently, both groups crossed Pten and Tsc2 heterozygous mice to investigate their roles in tumorigenesis.

Dr. Brendan Manning and colleagues (Harvard School of Public Health) found that the more benign nature of tumors lacking Tsc2 arises from the fact that a negative feedback loop exists to limit Akt signaling in these tumors. However, the loss of even one copy of Pten is sufficient to overcome this feedback mechanism, reactivate Akt, and dramatically enhance tumor severity.

Dr. Pier Paolo Pandolfi and colleagues (Memorial Sloan Kettering Cancer Center) also found that compound Pten/Tsc2 heterozygotes displayed accelerated tumorigenesis, with Tsc loss enhancing Pten-heterozygous tumor phenotypes. However, the authors also identified a non-reciprocal relationship between PTEN and TSC2 in tumorigenesis: TSC2 can suppress formation of specific tumors caused by Pten heterozygosity, but PTEN is haploinsufficient for repression of carcinogenesis resulting from Tsc2 heterozygosity. Specifically in the kidney, the researchers determined that Tsc2-heterozygous tumors need to loose the other copy of Tsc2 in order to become malignant.

While the studies do have some conflicting observations, which may be due to the fact that different strains of mice can display different tumor spectrums, the results put forth so far do have important clinical implications for the way in which tumor arising from such mutations are treated. Dr. Manning adds that "This attenuation of Akt signaling triggered upon loss of the TSC genes has been shown in cell culture experiments to be due to uncontrolled mTOR activity, as the mTOR inhibitor rapamycin can restore Akt activation. Our findings that relieving this feedback mechanism in vivo greatly enhances tumor growth in this mouse model of tuberous sclerosis complex, raises some concern about the use of rapamycin to treat this disease. Pending the results of ongoing clinical trials with rapamycin, these studies suggest that combination therapy with rapamycin and drugs that block receptor activation of Akt could be much more effective at treating TSC."

Cold Spring Harbor Laboratory

Related Tumors Articles from Brightsurf:

A viable vaccine for tough tumors
While immunotherapies work well for some cancers, others are immune-resistant and condemn patients to the severe side effects of long-term chemo treatment.

Women could conceive after ovarian tumors
Women receiving fertility-sparing surgery for treatment of borderline ovarian tumours were able to have children, a study from Karolinska Institutet in Sweden published in Fertility & Sterility shows.

Attacking tumors from the inside
A new technology that allows researchers to peer inside malignant tumors shows that two experimental drugs can normalize aberrant blood vessels, oxygenation, and other aspects of the tumor microenvironment in non-small cell lung cancer (NSCLC), helping to suppress the tumor's growth and spread, UT Southwestern researchers report.

Directing nanoparticles straight to tumors
Modern anticancer therapies aim to attack tumor cells while sparing healthy tissue.

A solid vaccine for liquid tumors
Acute myeloid leukemia (AML) is a deadly blood cancer that kills most of its victims within five years.

Evolutionarily novel genes work in tumors
A team of scientists from Peter the Great St. Petersburg Polytechnic University studied the evolutionary ages of human genes and identified a new class of them expressed in tumors -- tumor specifically expressed, evolutionarily novel (TSEEN) genes.

Identification of all types of germ cells tumors
Germ cell tumors were considered very heterogeneous and diverse, until recently.

Laser light detects tumors
A team of researchers from Jena presents a groundbreaking new method for the rapid, gentle and reliable detection of tumors with laser light.

Better prognosticating for dogs with mammary tumors
For dogs with mammary tumors, deciding a course of treatment can depend on a variety of factors, some of which may seem to contradict one another.

The evolution of brain tumors
Scientists from the German Cancer Research Center found in a recent study that only three different genetic alterations drive the early development of malignant glioblastomas.

Read More: Tumors News and Tumors Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to