Crosstalk between critical cell-signaling pathways holds clues to tumor invasion and metastasis

November 25, 2009

Two signaling pathways essential to normal human development - the Wnt/Wingless (Wnt) and epidermal growth factor receptor (EGFR) pathways - interact in ways that can promote tumor cell invasion and metastasis, researchers from The University of Texas M. D. Anderson Cancer Center report in the Nov. 25 issue of Molecular Cell.

This newly characterized interaction involves three signaling components known to correlate with invasive - activation of EGFR, elevated CK2 activity, and increased beta-catenin - T-cell factor/lymphoid enhancer factor (TCF/LEF-1) transcriptional activity.

"These findings highlight the importance of Wnt-independent and non-canonical activation of beta-catenin in tumor development," said senior author Zhimin Lu, MD, PhD, an associate professor in M. D. Anderson's Department of Neuro-Oncology. They also open up new possibilities for biomarkers that indicate prognosis or guide treatment.

Wnt Signaling and Cell-to-Cell Adhesion

is an intricate and precise process that enables cells to grow, differentiate (become specialized) and ultimately die (apoptosis). This orderly process is responsible for the normal development of organs and tissues. Alterations in the signaling within cells and between cells, however, can disrupt the cell-to-cell contact that helps keeps in place. Loss of cell-to-cell contact leads to tumor cell migration, invasion and metastasis.

The plays a critical role in cell development, proliferation and differentiation. Mutations in this important pathway leading to the activation of beta-catenin are responsible for many types of cancer, including . However, beta-catenin can also be activated in a mutation-independent manner in other cancers.

A key component of the Wnt pathway, beta-catenin combines with alpha-catenin and regulates cell-cell adhesion. It also interacts with alpha-catenin in the nucleus.

The alpha-catenin component of this beta-catenin/alpha-catenin complex has an inhibitory effect on beta-catenin that helps keep tumor cell migration and invasion in check. This inhibition is lost, however, when the EGFR pathway is activated. Upon activation, beta-catenin becomes untethered from alpha-catenin and translocates to the cell nucleus, where it increases expression of key target genes involved in tumor cell invasion and metastasis.

New Pathway Regulates Beta-Catenin Transactivation

The M. D. Anderson-led team made a surprising discovery: Beta-catenin also can travel to the nucleus via activation of the EGFR pathway-and it does so independently of Wnt signaling or mutations. The newly described pathway disrupts the beta-catenin/alpha catenin complex through an EGFR-extracellular receptor kinase (ERK)-protein kinase CK2- phosphorylation cascade. The investigators noted that this cascade culminates in the phosphorylation of alpha-catenin and ultimately promotes beta-catenin activation in the nucleus and subsequent tumor cell invasion.

The researchers found evidence of the newly identified pathway's clinical relevance when they examined human glioblastoma specimens. Specifically, levels of alpha-catenin phosphorylation correlated with levels of ERK activity and with grades of malignancy.

"Taken together, these findings demonstrate the importance of this pathway in tumor formation and progression," Dr. Lu said, "and they reveal potential markers for prognosis and therapeutics." Dr. Lu's lab is currently identifying genes downstream from beta-catenin that may be instrumental in tumor progression.

This research was supported by an American Cancer Society Research Scholar Award and grants from the Brain Tumor Society and Phi Beta Psi Sorority, an institutional research grant from M. D. Anderson Cancer Center; and a National Cancer Institute grant, all awarded to Lu.

Source: University of Texas M. D. Anderson Cancer Center (news : web)

Related Stories

Recommended for you

Cancer immunotherapy may work better in patients with specific genes

December 15, 2017
Cancer cells arise when DNA is mutated, and these cells should be recognized as "foreign" by the immune system. However, cancer cells have found ways to evade detection by the immune system.

Scientists pinpoint gene to blame for poorer survival rate in early-onset breast cancer patients

December 15, 2017
A new study led by scientists at the University of Southampton has found that inherited variation in a particular gene may be to blame for the lower survival rate of patients diagnosed with early-onset breast cancer.

'Bet hedging' explains the efficacy of many combination cancer therapies

December 14, 2017
The efficacy of many FDA-approved cancer drug combinations is not due to synergistic interactions between drugs, but rather to a form of "bet hedging," according to a new study published by Harvard Medical School researchers ...

Scientists unlock structure of mTOR, a key cancer cell signaling protein

December 14, 2017
Researchers in the Sloan Kettering Institute have solved the structure of an important signaling molecule in cancer cells. They used a new technology called cryo-EM to visualize the structure in three dimensions. The detailed ...

Liquid biopsy results differed substantially between two providers

December 14, 2017
Two Johns Hopkins prostate cancer researchers found significant disparities when they submitted identical patient samples to two different commercial liquid biopsy providers. Liquid biopsy is a new and noninvasive alternative ...

Testing the accuracy of FDA-approved and lab-developed cancer genetics tests

December 14, 2017
Cancer molecular testing can drive clinical decision making and help a clinician determine if a patient is a good candidate for a targeted therapeutic drug. Clinical tests for common cancer causing-mutations in the genes ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.