A Paradigm unleashes to target Ovarian Carcinoma

Chitra Roy, University of Calcutta

High-Grade Serous Ovarian Carcinoma (HGSOC) is one of the most common and deadliest types of ovarian cancer. This gynaecological malignancy is a type of tumour which arises from the ovary, fallopian tube, or peritoneum. The tumour microenvironment is very complex and 40% of this tumour mass contains Macrophages. Macrophages originate from circulating monocytes when they migrate to tissues where it gets exposed to local growth factors, pro-inflammatory cytokines and microbial products. These macrophages play a diverse role, like infection clearance, where it phagocytoses any pathogen which might have entered our system and thus, they are an important component of our innate immune system. Besides, macrophages also contribute to tissue damage during infection and inflammatory disease. One of their most remarkable features is Plasticity, where it can switch from one phenotype to the other. Depending upon the microenvironment, the macrophages can mount a specific phenotype. There are two major subpopulations of macrophages with different functions, including classically activated macrophage (CAM) / inflammatory (M1) and alternatively activated macrophage (AAM) / anti-inflammatory (M2), and this phenomenon of having two different phenotypes in M1/M2 is known as Macrophage Polarization. So, in response to the microenvironment, the macrophages adjust their polarization. 

In HGSOC, it is found that the tumour mass is mostly composed of alternatively activated macrophages (AAMs) having an anti-inflammatory response, which is responsible for promoting the development of the tumour. But how does AAMs contribute to this protumor effect? In HGSOC, AAMs secrete several soluble factors like MIP-1β, HB-EGF, and leptin, which helps in adhesion, proliferation and spreading of the ovarian cancer cells. Scientists have found that this AAMs on tumour originates from differentiating monocytes with a help of a cytokine called macrophage colony-stimulating factor (MCSF) and ultimately polarizes to this alternative phenotype AAM through IL-4 and IL-13. 

However, the portion which remained a mystery and unanswered is that what would be the role of the tumour cell in HGSOC to generate AAM from monocyte? Can identifying this mechanism of monocyte differentiation to macrophage and then polarizing to AAM phenotype help us in anyhow targeting these cancer cells? 

Well, to answer these questions, recently a team of researchers came up with a hypothesis that ovarian cancer cells could produce a unique set of soluble factors which can regulate the entire process. A combination of various experiments like in-vitro co-culture model, bioinformatics analysis of gene expression and phenotypic patterns, and screening of all probable candidate factors have led them to their findings. Scientific findings revealed that TGF-α is the novel factor in tumour cells which directly promotes macrophage differentiation. Their findings give a possibility shortly to target this factor and interfere with the tumour formation to slow down its progression.

Also read: SADS-CoV, a new type of coronavirus can infect humans

Reference: Fogg, K.C., Miller, A.E., Li, Y. et al. Ovarian cancer cells direct monocyte differentiation through a non-canonical pathway. BMC Cancer20, 1008 (2020). https://doi.org/10.1186/s12885-020-07513-w

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