Introduction
The phenomenon of cancer cell plasticity – also known as phenotypic switching– is the phenomenon of specific genotypes producing varying different phenotypes in response to changing external cues. It has been widely studied as a critical process involved in development and evolution, but more recently, its role in the progression of cancer, metastasis, and resistance to therapy has been recognized. Cancer stem cells (CSCs) are linked with the discovery of phenotypic plasticity in cancer cells gave which hypothesizes the presence of a subset of cells in the cancer cell population that exhibit plasticity, self-renewal, differentiation and tumorigenicity. In addition to driving cancer progression and metastasis, CSCs have also been implicated in drug resistance which contributes to the aggressive growth of the tumor. Furthermore, the CSC paradigm has been proposed as a model to explain the phenomenon of intra-tumoral heterogeneity, which refers to the phenotypic, genetic and functional heterogeneity within the cell population of a single tumor as well as between primary and metastatic tumors that arise as a result of intrinsic genetic programs and extracellular triggers.
Cancer cell plasticity and the resultant phenomena of CSCs and intra-tumoral heterogeneity are particularly relevant in solid cancers like breast cancer, in which studies have shown that plasticity could arise as a result of epithelial to mesenchymal transition (EMT)1 process induction that enables the carcinoma cells to metastasize to other locations within the body. Recent research has also found that factors such as genetic mutations, external stimuli or signaling from the tumor microenvironment as well as different environmental factors2 can trigger the transformation of already differentiated cells into CSCs, indicating the presence of plasticity even at various stages of differentiation in breast cancer3.
The molecular mechanisms that are related to the emergence of plasticity mainly attributes to intrinsic mechanisms involved in signaling pathways like Notch, MAPK, P13Kinase, Wnt, Hedgehog and STAT3 that work in tandem to control tumor cell dynamics and cell-to-cell communication. Cell-extrinsic factors like tumor microenvironment consisting of the immune system as well as tumor cell and the cancer-associated extracellular matrix (ECM) interaction, containing numerous receptors that have been strongly linked to providing a niche for cancer stem cells required for the development of plasticity.
In effective cancer treatment, therapy resistance poses a major problem, where tumor cells are initially responsive and develop resistance or have innate unresponsiveness to different anti-cancer drugs. Resistance in any type of cancer generally stems from several reasons - both genetic and epigenetic factors like cell plasticity, EMT, heterogeneity in cancer cells, mutations in different genes 4,5. Alongside intrinsic factors and pathways facilitating drug resistance, the role of extrinsic factors like tumor microenvironment is equally crucial. Dynamic changes in the microenvironment of tumor contributes vastly to drug resistance. We acknowledge that the microenvironment is an area of interest, but will not be covering it in this review though there are some excellent review articles on this subject6-8.
Common treatments that exist for different stages of cancer include surgery, hormonal therapy, radiation therapy, chemotherapy, targeted therapy and immunotherapy9. However, the major problem that stands in the way of an effective treatment regime is resistance to treatment. The need of the hour is to tackle the phenomenon of therapy resistance in cancer cells by targeting the intrinsic pathways as well as extrinsic factors that are seen to facilitate cell plasticity. Besides covering the mechanisms by which cell plasticity contributes to resistance, we will also focus on how we can target these pathways to negate therapeutic resistance with an overarching aim to obliterate cancer cells.