Promising treatment approach in pancreatic cancer
In the case of pancreatic cancer (pancreatic carcinoma), the prognosis for those affected is usually unfavorable. Because symptoms rarely appear in the early stages of the disease, this cancer is often only diagnosed at an advanced stage of the disease. Researchers are now reporting on a new way to combat this type of cancer.
Scientists at the University Medical Center Göttingen (UMG) have developed a new therapeutic approach pancreatic cancer discovered. The study results were published in the journals “Nature Cancer‘ and ‘Cancer Discovery’.
Diagnosis often only in advanced tumor stages
According to a recent Message According to the UMG, pancreatic cancer remains one of the deadliest cancers with an extremely poor prognosis. In more than a third of patients, the diagnosis is only made when the tumor is in an advanced stage.
Then the only treatment that can be considered is chemotherapy. However, the majority of patients are resistant to the chemotherapy available to date, and the therapy is not effective. In addition, the many different subtypes of pancreatic cancer make treatment even more difficult.
According to the experts, two molecular subgroups in particular differ significantly in their aggressiveness: the classic (CLA) and the basal-like (BL) subtype. Compared to the CLA subtype, the BL subtype has a poorer prognosis and high resistance to therapy.
subgroups characterized in more detail
Researchers from the Max Eder junior research group in the Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology at the UMG have now characterized these two subgroups of pancreatic cancer more precisely at the molecular level.
The aim of their investigations was to gain a better understanding of the role of immune cells in the response to therapy of the CLA and BL subtypes of pancreatic cancer. So far it has been known from clinical studies that so-called stromal immune components in these two subtypes determine the different prognosis and response to therapy.
However, it is still controversial whether stromal immune cells in these subtypes limit or promote their aggressiveness.
The findings and preclinical investigations of the Göttingen working group headed by Dr. Shiv K. Singh now open a promising approach for new strategies to treat the BL subtype of pancreatic cancer.
Opposite effects of two important immune cells
The Göttingen researchers examined how the two most important subtypes of pancreatic cancer (CLA and BL) interact with their environment and their connection to the degree of aggressiveness and resistance to therapy.
They focused on the inflammatory tumor-immune microenvironment. This is still a much-discussed area of research because it can have tumor-promoting or tumor-inhibiting effects.
On the one hand, effector T cells, especially cytotoxic T cells, constantly search our body for and kill potentially cancer-causing cells. On the other hand, it is also known that certain tumor-promoting macrophages (so-called TAMs) suppress these effector T cells and even supply the tumor with growth factors.
These opposing effects of two important immune cells on tumor growth pose a challenge that needs to be further investigated for the therapy of pancreatic cancer and its subtypes.
correlation proven
“We wanted to check whether the inflammatory immune system influences the identity of the subtype”, explains Dr. Shiv K. Singh, senior author of the publication. To do this, the researchers examined sequencing data from patients and found that inflammatory signaling pathways are enriched in tumors of the BL subtype.
“In particular, the cytokine tumor necrosis factor alpha (TNF-α for short), a messenger substance that promotes inflammation, and transcription factors (TFs) of the AP1 family are largely responsible for these inflammatory reactions.”according to the scientist.
“We were able to demonstrate the connection between TNF-α and the BL subtype in preclinical models. Treatment of cells of the CLA subtype with TNF-α promoted switching to an invasive BL phenotype. This suggests a functional role for TNF-α in the emergence of the unfavorable BL subtype.”
Prognosis could be improved
Despite the high TNF-α concentrations in tumor tissues, the researchers could not detect any TNF-α in isolated tumor cell lines, neither in cells of the CLA subtype nor in cells of the BL subtype.
However, they found that it was not the tumor cells but the immune cells, or more precisely macrophages, that produced the cytokine TNF-α in the tumor microenvironment. But how do BL tumor cells in particular, but not CLA tumors, attract these tumor-promoting macrophages?
To understand this, the scientists used state-of-the-art sequencing technologies and found that different TF complexes are responsible for regulating the genes that make up either the aggressive BL or the less aggressive CLA pancreatic cancer subtypes.
In addition, the research team identified pharmacological inhibition of the BL-specific TF complex as a promising treatment approach.
By inhibiting so-called BET proteins, which are essential for the function of this complex, the pro-inflammatory molecular processes of the aggressive BL subtype could be reversed and genes characteristic of the CLA subtype could be switched on here.
This therapy method in tumors of the BL subtype has improved the prognosis in preclinical models. (ad)
Author and source information
This text corresponds to the requirements of medical specialist literature, medical guidelines and current studies and has been checked by medical professionals.
Swell:
- University Medicine Göttingen – Georg-August-University: Understanding pancreatic cancer more precisely, (accessed: March 30, 2022), University Medicine Goettingen – Georg-August-University
- Mengyu Tu, Lukas Klein, Elisa Espinet, Theodoros Georgomanolis, Florian Wegwitz, Xiaojuan Li, Laura Urbach, Adi Danieli-Mackay, Stefan Küffer, Kamil Bojarczuk, Athanasia Mizi, Ufuk Günesdogan, Björn Chapuy, Zuguang Gu, Albrecht Neesse, Uday Kishore, Philipp Ströbel, Elisabeth Hessmann, Stephan A. Hahn, Andreas Trumpp, Argyris Papantonis, Volker Ellenrieder & Shiv K. Singh: TNF-α-producing macrophages determine subtype identity and prognosis via AP1 enhancer reprogramming in pancreatic cancer; in: Nature Cancer, (published: 15.11.2021), Nature Cancer
Important NOTE:
This article contains general advice only and should not be used for self-diagnosis or treatment. He can not substitute a visit at the doctor.