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.