Journal of Biochemistry and Cell Biology
Open Access

Tumorigenesis; Oncogenes; Tumor suppressor genes; Tumor microenvironment; Metastasis; Cancer therapy

Introduction

Cancer is a multifactorial disease characterized by uncontrolled cell growth and the ability to invade surrounding tissues [1]. The progression from normal cells to malignant tumors involves a series of genetic and epigenetic changes that enable cells to evade regulatory pathways governing cell growth, differentiation, and death. A critical understanding of these molecular events has led to the identification of specific genetic alterations that drive tumorigenesis, as well as the roles played by the tumor microenvironment in promoting cancer progression [2-4]. At the core of tumorigenesis lies the accumulation of mutations in key genes, including proto-oncogenes, tumor suppressor genes, and genes involved in DNA repair. These mutations can result in the activation of growth-promoting pathways or the loss of growth-inhibitory signals. Moreover, cancer cells often exploit signaling networks, such as the PI3K/Akt and MAPK pathways, to promote survival, proliferation, and resistance to therapies. The tumor microenvironment (TME) also plays an essential role in cancer progression. The TME includes stromal cells, immune cells, and extracellular matrix (ECM) components that interact with tumor cells to promote tumor growth, angiogenesis, and metastasis. These interactions are dynamic and can influence the response to therapy, which underscores the importance of considering the TME in the development of effective cancer treatments [5]. In this manuscript, we delve into the molecular mechanisms driving tumorigenesis, explore how genetic alterations contribute to the hallmarks of cancer, and discuss the emerging therapeutic strategies aimed at targeting these mechanisms.

Oncogenes and Tumor Suppressor Genes

The pathogenesis of cancer often begins with mutations that activate proto-oncogenes or inactivate tumor suppressor genes. Proto-oncogenes are normal genes that, when mutated or overexpressed, become oncogenes capable of promoting uncontrolled cell growth. Well-known examples include RAS and MYC, which are frequently mutated in various cancers [6]. Activation of the RAS pathway, for instance, leads to increased cell proliferation and survival, making it a key driver of tumorigenesis in cancers such as pancreatic, colon, and lung cancer. Tumor suppressor genes, on the other hand, function to regulate cell cycle progression and prevent uncontrolled cell division. Mutations or deletions of tumor suppressor genes, such as TP53, RB1, and PTEN, lead to the loss of these regulatory checkpoints, allowing cells to bypass normal growth controls. For example, TP53, often referred to as the “guardian of the genome,” is mutated in over 50% of human cancers, resulting in the loss of its function in apoptosis, DNA repair, and cell cycle arrest.

DNA Repair and Genomic Instability

The maintenance of genomic integrity is crucial for preventing cancer. Mutations in DNA repair pathways, such as those involving BRCA1 and BRCA2 in breast cancer, or MLH1 and MSH2 in colon cancer, lead to genomic instability and an increased accumulation of mutations [7]. These alterations compromise the ability of cells to repair DNA damage, contributing to the development of cancer. Tumors with defects in DNA repair mechanisms often exhibit microsatellite instability and may respond to specific therapies such as PARP inhibitors, which target defects in DNA repair pathways.

Epigenetic Modifications in Cancer

In addition to genetic mutations, epigenetic changes alterations in gene expression without changes to the underlying DNA sequence also play a critical role in tumorigenesis. DNA methylation, histone modifications, and non-coding RNAs can all influence gene expression patterns associated with tumorigenesis [8]. For example, hypermethylation of tumor suppressor gene promoters is a common feature in many cancers, leading to gene silencing and contributing to oncogenesis.

Signaling Pathways in Tumorigenesis

PI3K/Akt Pathway

The PI3K/Akt signaling pathway is one of the most commonly dysregulated pathways in cancer. Activation of PI3K leads to the phosphorylation and activation of Akt, which in turn regulates a wide variety of cellular processes including metabolism, survival, and growth. This pathway is frequently altered by mutations in PIK3CA, the gene encoding the catalytic subunit of PI3K, or by loss of PTEN, a negative regulator of PI3K. Constitutive activation of the PI3K/Akt pathway promotes cell survival and proliferation, making it an attractive target for cancer therapy.

MAPK/ERK Pathway

The MAPK/ERK pathway is another key signaling pathway that controls cell proliferation, differentiation, and survival. Activation of this pathway occurs through the binding of growth factors to receptor tyrosine kinases (RTKs), leading to the phosphorylation and activation of downstream signaling molecules, including RAS, RAF, and MEK. Mutations in RAS or BRAF are common in various cancers, particularly melanoma, colon cancer, and thyroid cancer. Inhibitors of BRAF and MEK are currently in clinical use and show promise in treating tumors with these mutations.

Wnt/β-Catenin Pathway

The Wnt/β-catenin pathway plays a critical role in regulating stem cell self-renewal, cell differentiation, and embryonic development. Aberrant activation of this pathway contributes to tumorigenesis by promoting the survival and proliferation of cancer stem cells. In many cancers, mutations in components of the Wnt pathway, such as APC, CTNNB1 (encoding β-catenin), or Axin, result in the stabilization and accumulation of β-catenin, which activates the transcription of genes that promote tumor growth. This pathway is a key target in the development of therapies for colorectal and other cancers.

Tumor Microenvironment (TME) and Metastasis

The tumor microenvironment (TME) is composed of various non-malignant cells, including cancer-associated fibroblasts (CAFs), immune cells, endothelial cells, and extracellular matrix (ECM) components. The TME plays a pivotal role in supporting tumor growth, angiogenesis, invasion, and metastasis. Tumor cells interact with the TME through signaling molecules such as vascular endothelial growth factor (VEGF), interleukins, and matrix metalloproteinases (MMPs), which facilitate tumor progression and the spread of cancer to distant organs. Metastasis is a multi-step process that involves local invasion of tumor cells into surrounding tissues, followed by intravasation into the bloodstream, extravasation into distant tissues, and colonization of secondary sites. The interaction between tumor cells and the TME is critical for each of these steps. Targeting the TME, for example through the inhibition of VEGF or MMPs, has emerged as a potential therapeutic strategy in cancer.

Results and Discussion

The molecular insights into tumorigenesis presented in this review underscore the complexity of cancer biology. Genetic mutations in oncogenes, tumor suppressor genes, and DNA repair pathways drive the initiation of cancer, while dysregulated signaling pathways sustain tumor growth and survival. The TME further promotes tumor progression and metastasis through dynamic interactions with tumor cells, offering additional therapeutic targets [9]. Recent advancements in precision medicine and targeted therapies have been shaped by our growing understanding of the molecular mechanisms of cancer. Drugs targeting specific mutations, such as EGFR inhibitors for lung cancer or BRAF inhibitors for melanoma, have shown clinical success. However, resistance to therapy remains a significant challenge, highlighting the need for combination therapies that target multiple pathways simultaneously. Furthermore, the emerging field of immunotherapy, including immune checkpoint inhibitors and CAR-T cell therapies, has shown promising results in certain cancers, particularly melanoma, lung cancer, and leukemia. These therapies aim to harness the immune system to specifically target cancer cells, and they have opened new avenues for treatment, especially in cancers with a high mutational burden [10]. Despite these advances, many cancers remain resistant to conventional therapies, and metastasis continues to be a major cause of cancer related death. Therefore, understanding the molecular interactions within the TME and identifying novel biomarkers for early detection and prognostication are critical for improving patient outcomes.

Acknowledgement

None

Conflict of Interest

None

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