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Kanazawa University Research: Important Signaling Pathway in Breast Cancer Revealed

KANAZAWA, Japan, January 23, 2019 /PRNewswire/ --

Researchers at Kanazawa University report in Proceedings of the National Academy of Sciences of the United States of America (PNAS) that a particular signaling pathway in breast-cancer tumors causes cancer cells to divide symmetrically, expanding the tumor. Inhibiting the pathway by drugs could become a strategy for eliminating the cancer cells. 

In breast cancer, one of the most common cancers in women, tumors contain a small amount of so-called cancer stem-like cells (CSCs). Being able to eliminate breast-cancer stem-like cells in a targeted way is essential for developing successful therapies - conventional treatments, such as chemotherapy or radiotherapy followed by drug intake, do not target CSCs. A better understanding of the processes generating CSCs in breast-cancer tumors is needed. Noriko Gotoh from Kanazawa University and colleagues have now uncovered a signaling pathway directly related to the proliferation of CSCs in breast cancer.

A property of stem cells is that they can self-renew and differentiate. Two types of stem-cell division can occur: symmetric or asymmetric (Fig. 1). In the former, two self-renewing stem cells are generated; in the latter, only one (and a differentiated cell). It is now believed that malignant CSCs have a higher tendency to divide symmetrically, thus increasing the number of CSCs. Gotoh and colleagues looked at how the microenvironment of CSCs, called the CSC niche, causes and sustains an increased rate of symmetric division.

The researchers started from the observation that a particular gene encoding a type of cytokine known as Semaphorin 3 (Sema3) was one of the most-expressed genes in the CSC niche (Fig. 2). (Cytokines are small proteins that, when released, affect the behavior of cells around them.) The production of Sema3 activates another protein, called MICAL3, the expression levels of which were also found to be high in the CSC niche.

Via a series of experiments in vitro, Gotoh and colleagues were able to confirm the critical roles of Sema3 and MICAL3 in breast cancer tumor development. Specifically, MICAL3 was shown to be required for tumor sphere formation (tumorigenicity is associated with spherical cell shapes). The scientists showed that Sema3-stimulated MICAL3 triggered a whole sequence of biomolecular interactions (a signaling pathway), ultimately resulting in induced symmetric division of CSCs, and hence their proliferation, in breast cancer (Fig. 3).

Having established this important pathway is highly relevant for developing treatments for breast cancer, because, quoting Gotoh and colleagues, "by inhibition of MICAL3 … or knockdown of each component in the signaling pathway, the symmetric cell division may be inhibited, leading to a reduction of breast-cancer stem-like cells."


Cancer stem cells 

A cancer stem (or stem-like) cell (CSC) is a cancerous cell with the property that it can differentiate in various cell types found in a particular cancer sample. CSCs are tumor-forming and resistant to radio- and chemotherapy. New cancer therapies targeting CSCs are being developed, as CSCs are involved in cancer metastasis and tumor relapse.

Noriko Gotoh from Kanazawa University and colleagues have now shown that a particular mechanism causes the CSCs in breast cancer to increasingly divide symmetrically, thereby each time creating two CSCs.

Signaling pathways 

A signaling pathway describes the signal transduction process in which a chemical or physical signal is transmitted through a cell as a sequence of molecular events - typically, biochemical reactions involving proteins. In a signaling pathway, groups of molecules work together to control cell functions, like cell division or cell death. The abnormal activation of a signaling pathway can sometimes lead to cancer. A strategy for preventing cancer due to abnormal signaling is to develop drugs that block the pathway.

Gotoh and colleagues have now discovered a signaling pathway that links the release of particular proteins to the stimulation of symmetrical CSC division in breast cancer.


Kana Tominaga, Hiroshi Minato, Takahiko Murayama, Asako Sasahara, Tatsunori Nishimura, Etsuko Kiyokawa, Hajime Kanauchi, Seiichiro Shimizu, Ayaka Sato, Kotoe Nishioka, Ei-ichi Tsuji, Masao Yano, Toshihisa Ogawa, Hideshi Ishii, Masaki Mori, Koichi Akashi, Koji Okamoto, Masahiko Tanabe, Kei-ichiro Tada, Arinobu Tojo, and Noriko Gotoh. Semaphorin signaling via MICAL3 induces symmetric cell division to expand breast cancer stem-like cells, Proc. Natl Acad. Sci. (January 8, 2019)

DOI: 10.1073/pnas.1806851116


About Nano Life Science Institute (WPI-NanoLSI)

Nano Life Science Institute (NanoLSI), Kanazawa University is a research center established in 2017 as part of the World Premier International Research Center Initiative of the Ministry of Education, Culture, Sports, Science and Technology. The objective of this initiative is to form world-tier research centers. NanoLSI combines the foremost knowledge of bio-scanning probe microscopy to establish 'nano-endoscopic techniques' to directly image, analyze, and manipulate biomolecules for insights into mechanisms governing life phenomena such as diseases.

About Kanazawa University

As the leading comprehensive university on the Sea of Japan coast, Kanazawa University has contributed greatly to higher education and academic research in Japan since it was founded in 1949. The University has three colleges and 17 schools offering courses in subjects that include medicine, computer engineering, and humanities.

The University is located on the coast of the Sea of Japan in Kanazawa - a city rich in history and culture. The city of Kanazawa has a highly respected intellectual profile since the time of the fiefdom (1598-1867). Kanazawa University is divided into two main campuses: Kakuma and Takaramachi for its approximately 10,200 students including 600 from overseas.

Further information
Hiroe Yoneda
Vice Director of Public Affairs
WPI Nano Life Science Institute (WPI-NanoLSI)
Kanazawa University
Kakuma-machi, Kanazawa 920-1192, Japan
Tel: +81-(76)-234-4550

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Last Updated: 23-Jan-2019