INTRODUCTION
Cancer is a condition where an aberrant mimicry of embryogenesis occurs to create an autonomous entity in one part of the body that has the potential to spread to other parts of the body and destroy its host. Metastasis, the process by which cancer cells escape the primary tumor site and colonize distant organs, is responsible for most cancer-related deaths. Intra-tumor interactions between the cellular and structural components of the tumor microenvironment (TME) regulate the aggressiveness and dissemination of malignant cells and promote immune evasion. At the secondary site, the TME also facilitates escape from dormancy to enhance metastatic tumor outgrowth.1 Cancer cells secrete growth factors and cytokines (including IL-6, IL-1β, TGF-β1, TGF-β2, FGF-2, and PDGF) that recruit and reprogram stromal cells, such as immune cells and fibroblasts, as well as enzymes that degrade and remodel the surrounding extracellular matrix (ECM) and basement membrane (BM), such as matrix metalloproteinases (MMPs).1
DISCUSSIONS
Cutaneous melanoma (CM) is a highly aggressive tumor derived from migrated neural crest cell melanoblasts, and is composed of transformed melanocytes with various genetic alterations. Its incidence has been steadily rising globally, affecting populations in Eastern and Western Europe, North America, and Australia/New Zealand. The genetic mutations are specific to the site, the degree of ultraviolet light exposure, and/or the specific genetic makeup of the host.2 When caught early, melanoma is potentially curable. With local recurrence and tumor progression, even with recent advances in immunotherapy the results are less optimistic and can be grim. While thicker tumors present a more immediate threat to the patient's wellbeing, statistically more deaths occur as a consequence of tumors initially considered thin (<1 mm).2,33 The goal of this paper is to review current research on tumorigenesis and genetic heterogeneity and to review some of the metrics available to assess tumor risk of dissemination.
Melanoma is initiated by the acquisition of single nucleotide variant (SNV) point mutations from ultraviolent (UV) light-induced DNA damage.3-5 Telomerase activation is fundamental in tumorigenesis.5,6 By maintaining telomere length, telomerase relieves a main barrier on cellular lifespan, enabling limitless proliferation driven by oncogenes. Highly recurrent mutations in the promoter of telomerase reverse transcriptase (TERT) is a common finding in tumors, noted to be found in over 50 cancer types. While TERT is expressed in stem cells, it is naturally silenced upon differentiation. TERT mutations occur early during cellular transformation and activate the TERT promoter by recurring transcription factors that do not normally regulate TERT gene expression.5,6 Telomere’s tumor suppression activity relies on the ability to initiate DNA damage-signaling pathways and downstream cellular events, ranging from cell cycle disruption to inflammation and apoptotic cell death.6,7 BRAF can induce senescence and cell cycle arrest in human nevi that do not suffer telomere attrition.8
Sequencing of 293 relevant cancer genes in 150 areas of 37 primary melanomas and their adjacent precursor lesions was performed.9 Precursor lesions were initiated by mutations of genes that are known to activate the mitogen-activated protein kinase pathway. Unequivocally benign lesions harbored BRAF V600E mutations exclusively, whereas those categorized as
Melanoma is initiated by the acquisition of single nucleotide variant (SNV) point mutations from ultraviolent (UV) light-induced DNA damage.3-5 Telomerase activation is fundamental in tumorigenesis.5,6 By maintaining telomere length, telomerase relieves a main barrier on cellular lifespan, enabling limitless proliferation driven by oncogenes. Highly recurrent mutations in the promoter of telomerase reverse transcriptase (TERT) is a common finding in tumors, noted to be found in over 50 cancer types. While TERT is expressed in stem cells, it is naturally silenced upon differentiation. TERT mutations occur early during cellular transformation and activate the TERT promoter by recurring transcription factors that do not normally regulate TERT gene expression.5,6 Telomere’s tumor suppression activity relies on the ability to initiate DNA damage-signaling pathways and downstream cellular events, ranging from cell cycle disruption to inflammation and apoptotic cell death.6,7 BRAF can induce senescence and cell cycle arrest in human nevi that do not suffer telomere attrition.8
Sequencing of 293 relevant cancer genes in 150 areas of 37 primary melanomas and their adjacent precursor lesions was performed.9 Precursor lesions were initiated by mutations of genes that are known to activate the mitogen-activated protein kinase pathway. Unequivocally benign lesions harbored BRAF V600E mutations exclusively, whereas those categorized as
