Why tumor cells leave home

June 11, 2013, Ludwig Maximilian University of Munich
Why tumor cells leave home
The invasion front of a colon carcinoma stained for beta-catenin. c-MYC and thus AP4 are regulated by the APC/beta-catenin signal pathway. The beta-catenin positive nuclei at the invasion front indicate increased activity of c-MYC and AP4 in these cells.

(Medical Xpress)—Malignant cells can escape from primary tumors and colonize new sites in other tissues. In a new study, LMU researchers show how the transcription factor AP4 promotes the development of such metastatic tumors.

Cell growth and cell division are markedly promoted by a master regulator called c-MYC, which functions as a transcription factor. The c- is essential for all processes that require vigorous , such as embryonic development and , and its function is normally kept under tight control. Indeed, failure of these can result in uninhibited cell proliferation – and the formation of tumors. This is underlined by the fact that levels of c-MYC are found to be abnormally high in about half of all human cancers.

The question of how c-MYC actually contributes to tumorigenesis is a major focus of research underway in Professor Heiko Hermeking's laboratory at LMU. In a new study, he and his group have identified a further strand in the web of interactions governed by c-MYC. "In an earlier study, we had found that c-MYC induces expression of the transcription factor AP4. But as it was not known precisely which genes are regulated by the latter, it remained unclear which of c-MYC's effects are mediated by AP4," Hermeking explains.

With the aid of genome-wide characterization of AP4's and direct functional tests, Hermeking's team have now carried out a systematic investigation of the actions of AP4 in the cell, and uncovered processes relevant to tumorigenesis and that are triggered by the protein.

Their most important finding is that AP4 plays an important role in facilitating the formation of metastases. Metastases are secondary tumors that become established when migrate from the primary tumor to other, often distant, tissues, and continue to proliferate there. "It turns out that AP4 initiates this process: It transforms locally proliferating, non-aggressive tumor cells into invasive metastasizing cells by inducing the so-called Epithelial-Mesenchymal Transition (EMT)," Hermeking explains. Reversible EMTs are a normal component of development. The term refers to a process in which adhesive cells growing in an ordered sheet on an underlying layer of connective tissue acquire the ability to dissociate themselves from their neighbors and penetrate through a so-called "basement membrane". Such cells are then free to migrate to other tissues, where they may either regain their epithelial character (during normal development) or, in the case of malignant cells, seed the formation of new tumors.

The new findings are of considerable clinical relevance. The researchers have shown that colon cancer patients whose tumor cells produced AP4 in large amounts were significantly more likely to develop metastases in the liver after surgical removal of the primary tumor, and had a poorer prognosis, than patients with lower levels of the transcription factor. "Conversely, we found that a specific pharmacological inhibitor of AP4 prevented the formation of metastases in a mouse model," Hermeking adds. Hence, these results indicate that AP4 is not only of diagnostic and prognostic value, but also represents a promising target for therapeutic interventions. The LMU team now plans to identify further targets of AP4 in tumor cells and determine whether other regulatory molecules, apart from c-MYC, act on the protein.

Explore further: Positive feedback and tumorigenesis: A vicious circle that promotes cell proliferation

More information: JEM 2013: jem.rupress.org/content/early/ … 3/06/04/jem.20120812

Related Stories

Positive feedback and tumorigenesis: A vicious circle that promotes cell proliferation

December 21, 2011
Cancer cells are essentially immortal. The acquisition of an unlimited capacity to divide – the process of immortalization - is a central event in the genesis of tumors. Normally, cells are subject to stringent mechanisms ...

Researchers discover master regulator in cancer metastasis

June 10, 2013
In the process of metastasis, the movement of cancer cells to different parts of the body, a specific master regulator gene plays a central role: a transcription factor named Sox4 activates a sequence of genes and triggers ...

Lymphoma therapy could deliver a double punch

April 30, 2012
B cell lymphomas are a group of cancers of that originate in lymphoid tissue from B cells, the specialized immune cell type that produces antibodies. The development of B cell lymphoma is associated with several known genetic ...

Aggressive cancer exploits MYC oncogene to amplify global gene activity

September 27, 2012
Whitehead Institute researchers have determined the mechanism used by c-Myc to increase the expression of all active genes in cancer cells. Elevated levels of c-Myc are linked to increased rates of metastasis, disease recurrence, ...

Scientists identify a critical tumor suppressor for cancer

August 2, 2012
Scientists from the Florida campus of The Scripps Research Institute have identified a protein that impairs the development and maintenance of lymphoma (cancer of the lymph nodes), but is repressed during the initial stages ...

Newly identified tumor suppressor provides therapeutic target for prostate cancer

April 1, 2013
Scientists at Sanford-Burnham Medical Research Institute (Sanford-Burnham) have identified how an enzyme called PKCζ suppresses prostate tumor formation. The finding, which also describes a molecular chain of events that ...

Recommended for you

Researchers artificially generate immune cells integral to creating cancer vaccines

August 14, 2018
For the first time, Mount Sinai researchers have identified a way to make large numbers of immune cells that can help prevent cancer reoccurrence, according to a study published in August in Cell Reports.

Chemicals found in vegetables prevent colon cancer in mice

August 14, 2018
Chemicals produced by vegetables such as kale, cabbage and broccoli could help to maintain a healthy gut and prevent colon cancer, a new study from the Francis Crick Institute shows.

Ovarian cancer genetics unravelled

August 14, 2018
Patterns of genetic mutation in ovarian cancer are helping make sense of the disease, and could be used to personalise treatment in future.

Lymphatic vessels unexpectedly promote the spread of cancer metastases

August 14, 2018
Lymphatic vessels actively contribute to the spread of cancer metastases from various organs. This unexpected realisation is the result of a joint study by researchers from ETH Zurich and the University Hospital Zurich as ...

Researchers uncover a major new vulnerability of childhood leukemia

August 14, 2018
Childhood leukemia is a diagnosis that no family ever wants to endure. While the treatment of most types of leukemia has improved steadily over the years, a few specific types remain very difficult to treat. One of these ...

Stress hormone is key factor in failure of immune system to prevent leukemia

August 14, 2018
The human stress hormone cortisol has been identified by scientists at the University of Kent as a key factor when the immune system fails to prevent leukemia taking hold.

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.