A study conducted by Professor Pranita Sarangi from Department of Biotechnology (DBT), IIT Roorkee has found that Fbln7-C, a C-terminal fragment of the adhesion protein Fibulin7, the latest member of the fibulin family of secreted glycoproteins, can delay the reprogramming process of macrophages present in the tumor tissues, also known as tumor associated macrophages (TAMs) while directly inhibiting the proliferation of cancer cells.
Reprogramming of immune cells in the cancer microenvironment is a critical step in the development of cancers. To hide from the recognition by the immune cells, cancer cells device multiple ways to suppress the immune cell functions. One of the cell types that is carefully reprogrammed by the cancer cells is the tumor-associated macrophages or TAMs.
As the cancer progress, the macrophages that are initially recruited into the cancer site to assist in the removal of the cancer cells get reprogrammed to produce certain protein substances that help the cancers to grow and spread to different parts of the body.
This study used various in vitro systems and an animal breast tumor model to highlight that Fbln7-C could help the macrophages to resist the reprogramming process and delay the conversion of anti-tumorigenic to pro-tumorigenic TAMs, while directly inhibiting the proliferation of cancer cells.
The study is published in The FEBS Journal, an official publication of the Federation of European Biochemical Societies. This work was also highlighted in a commentary published in the same journal by researchers from IIT Bombay. Prof Pranita Sarangi had received funds from the DBT-Govt of India (Innovative Young Biotechnologist Award-2017) for this work.
Her another study finds that Fbln7-C can regulate the inflammatory functions of human neutrophils, (cell type that works as the first line of defense of our immune system) and administration of Fbln7-C could improve survival in animals injected with Lipopolysaccharide (LPS), a cell wall content of gram-negative bacteria.
Hyperactivation and improper sequestration of neutrophils during systemic inflammatory diseases as seen in septic conditions could be dangerous and excessive release of antimicrobial substances and inflammatory mediators from active neutrophils could cause unwanted tissue damages leading to multi organ failure and death in such patients. Such symptoms are also seen in COVID-19 patients and targeting neutrophils and cytokine storm has been proposed to be associated with inflammatory responses in COVID-19 patients.
This research work provides evidence for the use od Fbln7-C or its bioactive fragments in systemic inflammatory conditions. This work was published in the CYTOKINE journal, the official journal of the International Cytokine and Interferon Society. Prof Pranita Sarangi had received funds from the DST-Govt of India for this work.
Fbln7 was first identified in the developing tooth and subsequently was shown to be expressed in several other tissues such as cartilage, bone, placenta, and eye. The research comes after a few years of study that showed Fbln7-C has a negative effect on blood vessel formation. Later, Prof. Sarangi, in association with Dr Yoshihiko Yamada from National Institutes of Health, USA, showed that Fbln7-C has a regulatory function on human monocytes.
"Fibulins are a group of secreted glycoproteins that play an instrumental role in cell adhesion, protein-protein interactions and regulation of various cellular functions such as cell morphology, motility, growth, and adhesion. A comparatively newer Fbln7 is highly expressed in tissues such as eye and the placenta that possesses specialized micro-environment for the regulation of immune cell activation and functions. My research identifies yet another role of Fbln7 in delaying macrophage reprogramming and cancer cell proliferation as well as regulating the inflammatory function of neutrophils," said Professor Pranita Sarangi, Department of Biotechnology, IIT Roorkee.
"It will be useful to further oncological and immunological research and designing therapeutics targeting immune cells functions under inflammatory and cancerous conditions. Our group is further studying this proteins and its peptides for designing suitable immunomodulatory therapeutics," Professor Pranita Sarangi added.
PhD students, Papiya Chakraborty (Recently joined as postdoctoral researcher at the National Institute of Ageing-National Institutes of Health, USA), Nibedita Dalpati, Shiba Prasad Dash, Chandra Bhan and Puneet Kumar from Prof Sarangi's laboratory carried out both neutrophil and TAM research under her supervision.
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