The abundant presence of an enzyme known as low molecular weight protein tyrosine phosphatase (LMWPTP) in tumor cells has long been considered an indicator of cancer aggressiveness and metastatic potential. It is also known to perform important functions in cells under normal conditions, participating both in the proliferation process and in the regulation of intracellular systems. Research continues on its role in the progression of cancer.
In Brazil, a group of researchers from the Bioassay and In Vitro Signal Transduction Laboratory at the University of Campinas, led by Professor Carmen Veríssima Ferreira-Halder, is studying the possibility of inhibiting this protein phosphatase to create new opportunities for monitoring and treating cancer and other diseases.
"We believe that inhibition of LMWPTP can contribute to the treatment of various diseases. In our case, the focus is cancer, but research shows that it is also associated with autoimmune diseases and diabetes, among others. “
Carmen Veríssima Ferreira-Halder, Professor, Laboratory of Bioassays and In Vitro Signal Transduction, University of Campinas
Ferreira-Halder was principal investigator of the Thematic Project “Low molecular weight protein tyrosine phosphatase in colorectal cancer: from the bench to the generation of the product”, supported by FAPESP and concluded in June 2020.
Phosphatase favors the action of intratumor proteins that help tumors to divide, migrate and metastasize. “That is why we say that it is a ‘hub’, in the sense that it controls several processes that together make tumor cells resistant to treatment and capable of migrating and establishing metastases,” he said.
A group review article published in Cell and Molecular Life Sciences describes 14 years of research on LMWPTP and its contribution to cancer treatment. “Our group was one of the first to show that this enzyme contributes to resistance to chemotherapy in leukemic cells,” said Ferreira-Halder. “We also found that the more advanced the tumor stage, the greater the amount of the enzyme.
With these findings as a basis, research carried out in collaboration with the group led by Professor Maikel Peppelenbosch at Erasmus University Medical Center in Rotterdam [Erasmus MC, Netherlands] validated the importance of LMWPTP for other types of cancer, such as prostate, colorectal and stomach cancer. This research showed us that LMWPTP not only weakens the response to chemotherapy drugs, but is also associated with an increased capacity for metastasis ”.
The review article, whose first author is Alessandra Valéria de Sousa Faria, also discusses the available substances that inhibit LMWPTP and the characteristics that hinder the development of drugs against it. Ferreira-Halder believes that it is not yet possible to talk about treatment based on LMWPTP inhibition, but the strategy can be used for other purposes.
“Our initial goal is to use this enzyme as a biomarker for the purpose of monitoring treatment, and also to classify patients in terms of disease severity. In my opinion, it can be done in a relatively short time, ”she said. “As for treatment, there is still a lot of work to be done. Professor Nunzio Bottini, from the University of California at San Diego [USA] filed a patent application for a highly effective inhibitor that can be administered orally. In fact, he and his group synthesized several inhibitors, but published only one. We may have a surprise and a drug will be developed more quickly. Who knows?”
The main challenges to be faced in the development of inhibitors are specificity – the drug must act specifically on LMWPTP, which is part of a family of about 100 very similar phosphatases – and stability, so that the drug remains active in the body. “Until Bottini and his group filed for a patent, all inhibitors acted on several members of the family,” said Ferreira-Halder.
Some of the substances mentioned in the review were developed for other purposes, but they also inhibit LMWPTP and can be used to treat cancer, according to Faria, who recently defended his doctoral thesis on how LMWPTP affects platelets, small fragments of cells in the bloodstream that play a key role in clotting.
Faria’s research on LMWPTP began with his role in colorectal cancer and platelet reaction in this microenvironment. “As our investigation of platelet biology progressed, we realized how much more knowledge of the enzyme’s action on platelets was needed,” she said.
The first part of the study consisted of verifying the action of LMWPTP and protein tyrosine phosphatase 1B (PTP1B) on platelets, both in metabolism and in function. The second focused on the influence of platelets on the expression of LMWPTP in cells.
“The goal was to find out to what extent tumor cells can ‘educate’ platelets to support certain events, such as metastases, for example, and conversely to what extent platelets ‘educate’ tumor cells to ensure their survival and proliferation,” he explained. Would make.
For Ferreira-Halder, the relationship seems to be two-way. “However, the action of tumor cells is likely to predominate. They practically program platelets to act in your favor,” she said.
Ferreira-Halder and her group have collaborated with Peppelenbosch since 2004, but work on the Thematic Project concluded in June began only in 2016, she recalled, adding that the experiments conducted by Emanuella Maria Barreto Fonseca and Cláudia de Lourdes Soraggi in the Peppelenbosch laboratory provided a vitally important work for the initial hypotheses. Fonseca was financed by a postdoctoral fellowship from FAPESP. Soraggi had the opportunity to take a training course abroad thanks to the support of the State University of Campinas (UNICAMP) through its Executive Vice-President for International Relations.
“In our research on the Thematic Project, we were able to investigate the action of this phosphatase from various angles and validate the hypothesis of its role in tumors other than chronic myeloid leukemia,” said Ferreira-Halder. “We wanted to discover the mechanism of its action and now we have a lot of information about that action – not only inside, but also outside the tumor, because we set out to see if LMWPTP also influenced the tumor microenvironment external to cancer cells.”
Other research interests of the group during the project included: extracellular vesicles (nanometric structures that play an important role in intercellular communication), with Stefano Piatto Clerici supported by FAPESP showing that the LMWPTP regulates these vesicles; platelets, studied by Faria, also with a scholarship FAPESP; and the TGF-beta signaling pathway, which is involved in several cellular processes, such as proliferation and differentiation, and was studied by Helon Guimarães Cordeiro.
The network of collaborators continued to expand, adding a specialist in platelet biology (Sheila Siqueira Andrade, from PlateInnove Biotech), and a hematologist and oncologist from Erasmus MC (Moniek de Maat and Gwenny Fuhler respectively).
According to Ferreira-Halder, the Thematic Project has already generated 15 publications (eight articles and two book chapters, in addition to five peer-reviewed articles), in addition to several other research fronts. A new project in the same line of research is being designed.
Faria, A.V. S., et al. (2020) Low molecular weight protein tyrosine phosphatase as a center for signaling cancer trademarks. Cell and Molecular Life Sciences. doi.org/10.1007/s00018-020-03657-x.