CANCER CONUNDRUM.

Over the past decade, majority of cancer studies and concepts focus on examination of activation and inactivation of critical genes. A substantial compendium on significance of oncogenes and tumor suppressor genes came to light with this. If cancer was a disease associated only with a set of aneuploidy cells, its cure and therapeutic elimination would have been achieved years ago.

In the recent past few decades, it has been elucidated that cancer is a collection of diverse cell population with a variety of genetic mutations. Tumor heterogenicity present intratumoral and intertumoral, makes the picture more complex. A heterogeneity keeps evolving in the tumor as the tumor grows and invades.

A host of other cells activated and recruited in the stroma or the local microenvironment also play an important role in cancer progression and growth. The cells that regulate different aspects of tumorogencity are fibroblasts, cells associated with innate and adaptive immunity—macrophages, dendritic cells, natural killer cells and mast cells. The blood and lymphatic vessels also play an important role. Along with the cancer and stromal cells in the epithelium and stroma, the end result is dictated by the molecules released by these cells.

A functional contribution in cancer development is related to the release of potent soluble mediators in the extracellular matrix (ECM) which regulate proliferation, migration, angiogenesis, tissue remodelling, metabolism, apoptosis, differentiation and is involved in genomic instability.

The three dimensional organization and architecture of the stroma and the ECM surrounding the tumor cells is very dynamic. The equilibrium and homeostasis in the stroma is orchestrated by the timely secretion of specific compounds. During cancer development the proteins and the other ECM molecules released, favor neoplastic proliferation supplemented by migration of cells and angiogenesis. A disturbance in a well-organized homeostatic tissue lead by a highly regulated multistage event, is the beginning of cancer initiation and progression. All the cells and molecules comprising a tumour, interact and engage in a highly regulated reciprocal dialogue which favors malignancy.

Multiple cells and events in a cancerous tissue show dynamism depending on the changing environment of the cancer milieu. The “Dynamism” of the cells, tissue or events can be missed if our studies are two dimensional. Understanding the diversity of tissue behaviour at different periods of time in the cancerous tissue might help us to understand and target the disease better. Many cells like fibroblasts, B and T lymphocytes and macrophages can actually act for the progression of a tumor or against its progression depending on the signalling pathways set up by the mediator in the microenvironment. Many such events can also favour tumor growth and invasion on one side and can cause tumor regression on the other. Such events are angiogenesis, inflammation associated with cancer, differentiation and epithelial-mesenchymal transition.[12] Depending upon the cascade of events or formation of cell types, it either leads to formation or regression of a tumor.

Tumour invasion involves complex interactions between the tumor and stromal cells. The cellular tumor microenvironment comprises chiefly of immune competent and inflammatory cells, endothelial cells and fibroblasts.[3] These cells can critically influence the multistep process of carcinogenesis and the malignant phenotype. In the early 1917s, tumor defence mechanism of lymphokine activated killer cells or macrophages were discovered. Soon the term tumor associated macrophage (TAM) came into existence describing the abnormal differentiation status of a macrophage associated with enhanced tumour growth and propagation, rather than a part of tumor regression or as a part of immune surveillance theory. In the twentieth century, the saga of macrophage revealed that the TAM recruitment in cancerous tissue, the numbers in which they participate and their biological asset, depend on the local chemokines secreted in the tumor microenvironment. Based on these dynamism, TAMs are classified into (M1)-proinflammatory macrophages and (M2)-suppressive macrophages. Hence TAMs can be associated with positive and negative prognosis in tumors.[45]

We present here the dynamism of TAMs in the form of M1 and M2 macrophages using the concept of yin and yang depicting two dissimilar events or things, which are complimenting and cascade into each other and is presented in the Figure 1.[5678] The dynamism of the cells is seen as two dissimilar halves but is integrated together in one circle completing the picture. Taoism explains the completeness of this picture by stating how two different, opposing parts can flow into each other, most of the time they might be even complementing each other and have a seed in each other, hence integrated together to complete the picture. The nature of Yin and Yang is not static, but they move to maintain an overall balance of the ‘whole’.

Figure 1

The dynamism of tumor associated macrophages depicted using concept of Yin and Yang