Review

Authors: Vlad Alexandru Ionescu, Gina Gheorghe, Nicolae Bacalbasa...

Colorectal cancer is the second leading cause of cancer-related mortality worldwide. Numerous pathophysiological mechanisms, such as abnormal cell proliferation, cell differentiation, resistance to apoptosis, invasion of structures adjacent to colorectal tumor cells, and distant metastasis, are involved in colorectal carcinogenesis. These processes are initiated by the complex interaction of a number of genetic and environmental factors, including sedentary lifestyle, obesity, alcohol consumption, smoking, or gut microbiota. Despite the significant progress achieved in the diagnostic and therapeutic management of patients with colorectal cancer, there has been recently a noteworthy increase in the incidence of colorectal cancer in individuals below the age of 50 years. Early-onset colorectal cancer has a different frequency of oncogenic mutations, a higher prevalence of mucinous histology, a distinct deoxyribonucleic acid (DNA) methylation profile, a more distal location, and lower survival rates. A significant improvement in the prognosis of these patients can be achieved through the detection and removal of modifiable risk factors, along with the implementation of personalized screening strategies for individuals at high risk for this malignancy. Furthermore, gaining comprehension of the pathophysiological mechanisms by which these risk factors contribute to the process of oncogenesis may facilitate the discovery of novel therapeutic targets.

Topics: Humans; Middle Aged; Carcinogenesis; Cell Transformation, Neoplastic; Risk Factors; Alcohol Drinking; Colorectal Neoplasms

PubMed: 37763765
DOI: 10.3390/medicina59091646

Review

Authors: Arianna Calcinotto, Jaskaren Kohli, Elena Zagato...

Cellular senescence is a permanent state of cell cycle arrest that occurs in proliferating cells subjected to different stresses. Senescence is, therefore, a cellular defense mechanism that prevents the cells to acquire an unnecessary damage. The senescent state is accompanied by a failure to re-enter the cell cycle in response to mitogenic stimuli, an enhanced secretory phenotype and resistance to cell death. Senescence takes place in several tissues during different physiological and pathological processes such as tissue remodeling, injury, cancer, and aging. Although senescence is one of the causative processes of aging and it is responsible of aging-related disorders, senescent cells can also play a positive role. In embryogenesis and tissue remodeling, senescent cells are required for the proper development of the embryo and tissue repair. In cancer, senescence works as a potent barrier to prevent tumorigenesis. Therefore, the identification and characterization of key features of senescence, the induction of senescence in cancer cells, or the elimination of senescent cells by pharmacological interventions in aging tissues is gaining consideration in several fields of research. Here, we describe the known key features of senescence, the cell-autonomous, and noncell-autonomous regulators of senescence, and we attempt to discuss the functional role of this fundamental process in different contexts in light of the development of novel therapeutic targets.

Topics: Aging; Animals; Cell Proliferation; Cell Transformation, Neoplastic; Cellular Senescence; Humans; Neoplasms; Wound Healing

PubMed: 30648461
DOI: 10.1152/physrev.00020.2018

Review

Authors: Yuhe Huang, Weiqi Hong, Xiawei Wei...

Epithelial-mesenchymal transition (EMT) is an essential process in normal embryonic development and tissue regeneration. However, aberrant reactivation of EMT is associated with malignant properties of tumor cells during cancer progression and metastasis, including promoted migration and invasiveness, increased tumor stemness, and enhanced resistance to chemotherapy and immunotherapy. EMT is tightly regulated by a complex network which is orchestrated with several intrinsic and extrinsic factors, including multiple transcription factors, post-translational control, epigenetic modifications, and noncoding RNA-mediated regulation. In this review, we described the molecular mechanisms, signaling pathways, and the stages of tumorigenesis involved in the EMT process and discussed the dynamic non-binary process of EMT and its role in tumor metastasis. Finally, we summarized the challenges of chemotherapy and immunotherapy in EMT and proposed strategies for tumor therapy targeting EMT.

Topics: Cell Transformation, Neoplastic; Epigenesis, Genetic; Epithelial-Mesenchymal Transition; Humans; Immunotherapy; Neoplasm Metastasis; Neoplasms

PubMed: 36076302
DOI: 10.1186/s13045-022-01347-8

Review

Authors: Thomas N Seyfried, Leanne C Huysentruyt

Metastasis involves the spread of cancer cells from the primary tumor to surrounding tissues and to distant organs and is the primary cause of cancer morbidity and mortality. In order to complete the metastatic cascade, cancer cells must detach from the primary tumor, intravasate into the circulatory and lymphatic systems, evade immune attack, extravasate at distant capillary beds, and invade and proliferate in distant organs. Currently, several hypotheses have been advanced to explain the origin of cancer metastasis. These involve an epithelial mesenchymal transition, an accumulation of mutations in stem cells, a macrophage facilitation process, and a macrophage origin involving either transformation or fusion hybridization with neoplastic cells. Many of the properties of metastatic cancer cells are also seen in normal macrophages. A macrophage origin of metastasis can also explain the long-standing "seed and soil" hypothesis and the absence of metastasis in plant cancers. The view of metastasis as a macrophage metabolic disease can provide novel insight for therapeutic management.

Topics: Cell Adhesion; Cell Transformation, Neoplastic; Epithelial-Mesenchymal Transition; Humans; Macrophages; Mutation; Neoplasm Metastasis; Neoplasms

PubMed: 23237552
DOI: 10.1615/critrevoncog.v18.i1-2.40

Review

Authors: Joan Massagué, Karuna Ganesh

Metastasis is initiated and sustained through therapy by cancer cells with stem-like and immune-evasive properties, termed metastasis-initiating cells (MIC). Recent progress suggests that MICs result from the adoption of a normal regenerative progenitor phenotype by malignant cells, a phenotype with intrinsic programs to survive the stresses of the metastatic process, undergo epithelial-mesenchymal transitions, enter slow-cycling states for dormancy, evade immune surveillance, establish supportive interactions with organ-specific niches, and co-opt systemic factors for growth and recurrence after therapy. Mechanistic understanding of the molecular mediators of MIC phenotypes and host tissue ecosystems could yield cancer therapeutics to improve patient outcomes. SIGNIFICANCE: Understanding the origins, traits, and vulnerabilities of progenitor cancer cells with the capacity to initiate metastasis in distant organs, and the host microenvironments that support the ability of these cells to evade immune surveillance and regenerate the tumor, is critical for developing strategies to improve the prevention and treatment of advanced cancer. Leveraging recent progress in our understanding of the metastatic process, here we review the nature of MICs and their ecosystems and offer a perspective on how this knowledge is informing innovative treatments of metastatic cancers.

Topics: Cell Transformation, Neoplastic; Ecosystem; Humans; Neoplasm Metastasis; Neoplasms; Neoplastic Stem Cells; Tumor Microenvironment

PubMed: 33811127
DOI: 10.1158/2159-8290.CD-21-0010

Review

Authors: Defne Bayik, Justin D Lathia

Cellular heterogeneity and an immunosuppressive tumour microenvironment are independent yet synergistic drivers of tumour progression and underlie therapeutic resistance. Recent studies have highlighted the complex interaction between these cell-intrinsic and cell-extrinsic mechanisms. The reciprocal communication between cancer stem cells (CSCs) and infiltrating immune cell populations in the tumour microenvironment is a paradigm for these interactions. In this Perspective, we discuss the signalling programmes that simultaneously induce CSCs and reprogramme the immune response to facilitate tumour immune evasion, metastasis and recurrence. We further highlight biological factors that can impact the nature of CSC-immune cell communication. Finally, we discuss targeting opportunities for simultaneous regulation of the CSC niche and immunosurveillance.

Topics: Animals; Humans; Neoplasms; Neoplastic Processes; Neoplastic Stem Cells; Tumor Escape; Tumor Microenvironment

PubMed: 34103704
DOI: 10.1038/s41568-021-00366-w

Review

Authors: Anatoli Kustanovich, Ruth Schwartz, Tamar Peretz...

Tumor-specific, circulating cell-free DNA in liquid biopsies is a promising source of biomarkers for minimally invasive serial monitoring of treatment responses in cancer management. We will review the current understanding of the origin of circulating cell-free DNA and different forms of DNA release (including various types of cell death and active secretion processes) and clearance routes. The dynamics of extracellular DNA in blood during therapy and the role of circulating DNA in pathophysiological processes (tumor-associated inflammation, NETosis, and pre-metastatic niche development) provide insights into the mechanisms that contribute to tumor development and metastases formation. Better knowledge of circulating tumor-specific cell-free DNA could facilitate the development of new therapeutic and diagnostic options for cancer management.

Topics: Animals; Biomarkers, Tumor; Cell Transformation, Neoplastic; Cell-Free Nucleic Acids; Circulating Tumor DNA; DNA, Neoplasm; Humans; Liquid Biopsy; Neoplasms; Organ Specificity

PubMed: 30990132
DOI: 10.1080/15384047.2019.1598759

Review

Authors: Tamara T Lah, Metka Novak, Barbara Breznik...

Brain, the major organ of the central nervous system controls and processes most of body activities. Therefore, the most aggressive brain tumor - glioblastoma and metastases from other organs to the brain are lethal leaving the patients with very short time of survival. The brain tissue landscape is very different from any other tissues and the specific microenvironment, comprising stem cells niches and blood-brain barrier, significantly influences the low rate of glioblastoma metastasis out of the brain, but better accommodates brain-invading cancer. In contrast to low frequency (0.5%) of all glioblastoma metastases, 10%-45% of other primary cancers do metastasize to the brain. This review addresses general cellular and molecular pathways that are to some extent similar in both types of metastases, involving circulating tumor cells (CTCs) with cancer stem cells (CSCs) characteristics, and metastatic niches. The invasion is a dynamic process involving reversible epithelial-to-mesenchymal (EMT) cell process, creating a transient gradient state that is inter-connected with epigenetic plasticity of the metastasizing (m)CSCs. These cells can switch between stationary, low proliferating/dormant state to a migratory, mesenchymal-like state. Settling in their respective niches as dormant CSCs in the secondary organ is a common feature in all types of metastases. In glioblastoma metastasis, the malignant mGSC cells express markers of mesenchymal GSC subtype (MES-GSC), such as CD44 and YK-40 and their major obstacle seems to be propagating in the in various organs' microenvironments, different from the niches that home GSCs in the primary glioblastoma. Focusing on one stromal component in the glioblastoma niches, the mesenchymal stem cells (MSCs), we report herein on their differential effects on glioblastoma cells, highly depending on their genetic subtype. On the other hand, in brain metastases, the major hindrance to metastatic progression of mCSCs seem to be crossing the blood-brain-barrier. Novel therapeutic approaches for brain metastases from various cancer types are advancing slowly, and the general trends involve targeting metastatic sub-clones and selective determinants of their niches. The update on the four most common brain metastases from lung, breast, melanoma and colorectal carcinoma is presented.

Topics: Animals; Biomarkers; Brain Neoplasms; Disease Management; Disease Progression; Disease Susceptibility; Glioblastoma; Humans; Neoplasm Metastasis; Neoplastic Cells, Circulating; Neoplastic Stem Cells; Stem Cell Niche; Stromal Cells; Tumor Microenvironment

PubMed: 31654711
DOI: 10.1016/j.semcancer.2019.10.010

Review

Authors: Wei Lu, Yibin Kang

Epithelial-to-mesenchymal transition (EMT) and its reversed process, mesenchymal-to-epithelial transition (MET), are fundamental processes in embryonic development and tissue repair but confer malignant properties to carcinoma cells, including invasive behavior, cancer stem cell activity, and greater resistance to chemotherapy and immunotherapy. Understanding the molecular and cellular basis of EMT provides fundamental insights into the etiology of cancer and may, in the long run, lead to new therapeutic strategies. Here, we discuss the regulatory mechanisms and pathological roles of epithelial-mesenchymal plasticity, with a focus on recent insights into the complexity and dynamics of this phenomenon in cancer.

Topics: Animals; Cell Plasticity; Cell Transformation, Neoplastic; Embryonic Development; Epithelial-Mesenchymal Transition; Fibroblasts; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Neoplastic Stem Cells; Neovascularization, Pathologic

PubMed: 31063755
DOI: 10.1016/j.devcel.2019.04.010

Review

Authors: Héctor Peinado, Haiying Zhang, Irina R Matei...

It is well established that organs of future metastasis are not passive receivers of circulating tumour cells, but are instead selectively and actively modified by the primary tumour before metastatic spread has even occurred. Sowing the 'seeds' of metastasis requires the action of tumour-secreted factors and tumour-shed extracellular vesicles that enable the 'soil' at distant metastatic sites to encourage the outgrowth of incoming cancer cells. In this Review, we summarize the main processes and new mechanisms involved in the formation of the pre-metastatic niche.

Topics: Animals; Humans; Neoplasm Metastasis; Neoplasms; Neoplastic Cells, Circulating; Tumor Microenvironment

PubMed: 28303905
DOI: 10.1038/nrc.2017.6