• cancer
• cellular plasticity
• epithelial-mesenchymal transition
• regulatory factors
• tumor microenvironment

• Epithelial-Mesenchymal Transition/genetics
• Humans
• Neoplasms/pathology
• Neoplasms/metabolism
• Neoplasms/genetics
• Animals
• Disease Progression
• Epigenesis, Genetic
• Tumor Microenvironment
• Signal Transduction
• Gene Expression Regulation, Neoplastic

• Cell reprograming
• Mixed adeno-neuroendocrine cancer
• Mixed adenocarcinoma and neuroendocrine carcinoma
• Mixed neuroendocrine and non-neuroendocrine neoplasm
• Tumor plasticity

• Cancer cell plasticity
• Cancer stem cell
• Chemoresistance
• Gut microbiota
• Immune resistance
• Metabolites

• Humans
• Gastrointestinal Microbiome
• Cell Plasticity
• Drug Resistance, Neoplasm
• Neoplasms/drug therapy
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use

• 1106/UGC NET/JULY2016 University Grants Commission
• CSIR-FIRST [6/1/FIRST/2020-RPPBDD-TMD-SeMI] MLP-0299 Council of Scientific and Industrial Research, India
• MLP-250 Central Food Technological Research Institute, Council of Scientific and Industrial Research

• Biomarker
• IRBIT
• Lung cancer stem cells (LCSC)
• NSCLC

• tumour-suppressor proteins
• breast cancer
• tumour heterogeneity
• cancer models

• Hallmarks of cancer
• Non-mutational epigenetic reprogramming
• Phenotypic plasticity
• Polymorphic microbiomes
• Senescence
• Transcription factors

High grade anal intraepithelial neoplasia due to human papilloma viral (HPV) infections is a precursor lesion for squamous cell carcinoma especially in high risk populations. Frequent examination and anal biopsies remain unpopular with patients; moreover they are also risk factors for chronic pain, scarring and sphincter injury. There is lack of uniform, surveillance methods and guidelines for anal HPV specifically the intervals between exam and biopsies. The aim of this editorial is to discuss the intervals for surveillance exam and biopsy, based on specific HPV related biomarkers? Currently there are no published randomized controlled trials documenting the effectiveness of anal screening and surveillance programs to reduce the incidence, morbidity and mortality of anal cancers. In contrast, the currently approved screening and surveillance methods available for HPV related cervical cancer includes cytology, HPV DNA test, P16 or combined P16/Ki-67 index and HPV E/6 and E/7 mRNA test. There are very few studies performed to determine the efficacy of these tests in HPV related anal pre-cancerous lesions. The relevance of these biomarkers is discussed in this editorial. Longitudinal prospective research is needed to confirm the effectiveness of these molecular biomarkers that include high risk HPV serotyping, P16 immuno-histiochemistry and E6/E7 mRNA profiling on biopsies to elucidate and establish surveillance guidelines.

• Anal cancer
• Biomarkers
• P16
• E6/E7 mRNA
• Human papilloma viral DNA

• EMT
• MET
• embryonic
• tissue repair
• tumorigenesis

• epithelial-mesenchymal plasticity
• lineage plasticity
• metastasis
• therapy resistance
• tumor progression

• SB/S2/RJN/182/2014 Science and Engineering Research Board
• SB/S2/RJN-049/ 2018 Science and Engineering Research Board

Cancer stem cells (CSCs) are a minority subset of cancer cells that can drive tumor initiation, promote tumor progression, and induce drug resistance. CSCs are difficult to eliminate by conventional therapies and eventually mediate tumor relapse and metastasis. Moreover, recent studies have shown that CSCs display plasticity that renders them to alter their phenotype and function. Consequently, the varied phenotypes result in varied tumorigenesis, dissemination, and drug-resistance potential, thereby adding to the complexity of tumor heterogeneity and further challenging clinical management of cancers. In recent years, tumor microenvironment (TME) has become a hotspot in cancer research owing to its successful application in clinical tumor immunotherapy. Notably, emerging evidence shows that the TME is involved in regulating CSC plasticity. TME can activate stemness pathways and promote immune escape through cytokines and exosomes secreted by immune cells or stromal cells, thereby inducing non-CSCs to acquire CSC properties and increasing CSC plasticity. However, the relationship between TME and plasticity of CSCs remains poorly understood. In this review, we discuss the emerging investigations on TME and CSC plasticity to illustrate the underlying mechanisms and potential implications in suppressing cancer progression and drug resistance. We consider that this review can help develop novel therapeutic strategies by taking into account the interlink between TME and CSC plasticity.

• cancer progression
• cancer stem cell
• plasticity
• resistance
• tumor microenvironment

Cellular heterogeneity poses an immense therapeutic challenge in cancer due to a constant change in tumor cell characteristics, endowing cancer cells with the ability to dynamically shift between states. Intra-tumor heterogeneity is largely driven by cancer cell plasticity, demonstrated by the ability of malignant cells to acquire stemness and epithelial-to-mesenchymal transition (EMT) properties, to develop therapy resistance and to escape dormancy. These different aspects of cancer cell remodeling are driven by intrinsic as well as by extrinsic signals, the latter being dominated by factors of the tumor microenvironment. As part of the tumor milieu, chronic inflammation is generally regarded as a most influential player that supports tumor development and progression. In this review article, we put together recent findings on the roles of inflammatory elements in driving forward key processes of tumor cell plasticity. Using breast cancer as a representative research system, we demonstrate the critical roles played by inflammation-associated myeloid cells (mainly macrophages), pro-inflammatory cytokines [such as tumor necrosis factor α (TNFα) and interleukin 6 (IL-6)] and inflammatory chemokines [primarily CXCL8 (interleukin 8, IL-8) and CXCL1 (GROα)] in promoting tumor cell remodeling. These inflammatory components form a common thread that is involved in regulation of the three plasticity levels: stemness/EMT, therapy resistance, and dormancy. In view of the fact that inflammatory elements are a common denominator shared by different aspects of tumor cell plasticity, it is possible that their targeting may have a critical clinical benefit for cancer patients.

• cytokines/chemokines
• dormancy
• epithelial-to-mesenchymal transition
• inflammation
• macrophages
• stemness
• therapy resistance
• tumor cell plasticity

• activated and silenced cancer stem cell niche
• cancer cell fusion
• cancer stem cells
• epithelial-mesenchymal transition
• mesenchymal stroma/stem-like cells
• post-hybrid selection process
• retrodifferentiation
• tumor plasticity

Intratumoral heterogeneity is considered the major cause of drug resistance and hence treatment failure in cancer patients. Tumor cells are known for their phenotypic plasticity that is the ability of a cell to reprogram and change its identity to eventually adopt multiple phenotypes. Tumor cell plasticity involves the reactivation of developmental programs, the acquisition of cancer stem cell properties and an enhanced potential for retro- or transdifferentiation. A well-known transdifferentiation mechanism is the process of epithelial-mesenchymal transition (EMT). Current evidence suggests a complex interplay between EMT, genetic and epigenetic alterations, and various signals from the tumor microenvironment (TME) in shaping a tumor cell’s plasticity. The vulnerabilities exposed by cancer cells when residing in a plastic or stem-like state have the potential to be exploited therapeutically, i.e., by converting highly metastatic cells into less aggressive or even harmless postmitotic ones.

Intratumoral heterogeneity is considered the major cause of drug unresponsiveness in cancer and accumulating evidence implicates non-mutational resistance mechanisms rather than genetic mutations in its development. These non-mutational processes are largely driven by phenotypic plasticity, which is defined as the ability of a cell to reprogram and change its identity (phenotype switching). Tumor cell plasticity is characterized by the reactivation of developmental programs that are closely correlated with the acquisition of cancer stem cell properties and an enhanced potential for retrodifferentiation or transdifferentiation. A well-studied mechanism of phenotypic plasticity is the epithelial-mesenchymal transition (EMT). Current evidence suggests a complex interplay between EMT, genetic and epigenetic alterations, and clues from the tumor microenvironment in cell reprogramming. A deeper understanding of the connections between stem cell, epithelial–mesenchymal, and tumor-associated reprogramming events is crucial to develop novel therapies that mitigate cell plasticity and minimize the evolution of tumor heterogeneity, and hence drug resistance. Alternatively, vulnerabilities exposed by tumor cells when residing in a plastic or stem-like state may be exploited therapeutically, i.e., by converting them into less aggressive or even postmitotic cells. Tumor cell plasticity thus presents a new paradigm for understanding a cancer’s resistance to therapy and deciphering its underlying mechanisms.

• cancer cell fusion
• cancer stem cells
• epithelial-mesenchymal transition
• mesenchymal stroma/stem-like cells
• plasticity
• post-hybrid selection process
• retrodifferentiation
• transdifferentiation
• tumor heterogeneity
• tumor therapy