Cancer

Cancer has a complex and multistep pathogenesis characterized by cell properties acquired during the transition from normal to cancerous to sustain proliferation, evade growth suppressors, resist cell death, enable replicative immortality, induce angiogenesis, and more. Dysfunctional cellular signaling pathways due to cancer-related genetic and epigenetic alterations influence many of these cancer traits and are potential targets for cancer therapeutics. (1)

Cancer is a heterogeneous disease in which cells divide and grow uncontrollably, continuously, and rapidly so that they invade and spread to surrounding tissues and organs (2). Often these properties arise due to  abnormalities in genes involved in cell regulation, including proto-oncogenes, tumor suppressor genes, and DNA repair genes (3). These cancer cells have also accumulated abnormalities that make them unresponsive to signals that control cell behavior (4). These characteristics may be caused by errors in cell division, inherited mutations, nutritional deficiency, exposure to substances that damage or alter DNA (carcinogens), aging, and chronic inflammation (3, 5).

All cancer cells share well-defined features that explain their transition and differentiate them from normal cells. These biological features are called the hallmarks of cancer, and they include sustained proliferation, growth suppressor evasion, resistance to cell death, replicative immortality, sustained angiogenesis, and invasion and metastasis (6).

Scientists have also observed two emerging features as well as characteristics that facilitate the development of hallmark characteristics called enabling characteristics. These emerging features include reprogrammed energy metabolism and immune system avoidance, while the enabling characteristics include genome instability and mutation and tumor-promoting inflammation (6).

Genetic and epigenetic changes in cancer are responsible for the dysregulation of cellular signal pathways, which then contribute to the characteristics and progression of cancer. These signaling pathways, including the PI3K/Akt, NF-κB, and JAK/STAT are usually involved in cell functions, including cell growth, division, survival, motility, and death (7).

Pathways involved in the six hallmarks of cancer

Sustained proliferative signaling

Sustained proliferative signaling is a foundational characteristic of cancer cells. Normal cells require a growth factor signal before activating signaling cascades that cause them to grow. In cancer cells, this process is dysregulated; mutations or epigenetic changes result in the activation of pathways that promote proliferation and inhibition of regulated cell death pathways, facilitating unrestrained proliferation (3, 8).

Therefore, the pathways involved in cancer cell proliferation have become a focus for potential cancer treatments. These pathways include HIF-1, PI3K/Akt, NF-κB, and IGFR1 signaling (8).

Growth suppressor evasion

Another prominent feature of cancer cells is their ability to evade growth suppressors. This feature is complementary to sustained proliferative signaling in the survival and proliferation of cancer cells (9).

In normal cells, tumor suppressor signaling pathways such as TP53, Rb, and PTEN efficiently work to inhibit or slow down cell growth and proliferation. Genetic and epigenetic alterations in tumor cells lead to the deletion or loss of function mutation of these tumor suppressor genes and the activation and gain-of-function mutation of growth-promoting genes, enabling cancer cells to replicate unchecked (10). 

For instance, PTEN regulates the PI3K/Akt pathway, which is involved in cell growth, proliferation, and survival. Loss of function PTEN mutation or PTEN deletion is present in 50% of tumors. The loss of PTEN leads to unrestrained PI3K/Akt signaling, promoting tumor growth. The Hippo pathway, another negative growth regulator, works by inhibiting YAP/TAZ, a growth-promoting signaling pathway, and loss of Hippo or hyperactivation of YAP/TAZ has been shown to lead to hyperplasia and tumorigenesis in animal studies (9).

Targets that inhibit growth-promoting pathways and promote anti-growth signals are promising cancer interventions. 

Resistance to Cell Death

Regulated cell death (RCD),  also called programmed cell death (PCD) when occuring under normal physiological conditions, refers to the tightly controlled death of cells, via various signaling pathways. It helps to maintain tissue homeostasis and restore biological equilibrium in response to stress. Regulated cell death may exist in various forms, including apoptosis, autophagy, necroptosis, pyroptosis, ferroptosis, parthanatos, alkaliptosis, oxeiptosis, entosis, NETosis, and Lysosome-dependent cell death (LCD) (11, 12). The dysregulation of any of these cell death pathways leads to cell death resistance in cancer and also underlies other diseases.

Apoptosis is well-recognized as a pivotal regulated cell death mode that eliminates irreparably damaged cells, regulates cell fate, and maintains internal stability. It has two pathways, extrinsic and intrinsic pathways, regulated by multiple genes. The extrinsic pathway is modulated by death receptors, including FAS, TNFRSF1A, and DR4/5, and the intrinsic pathway is mediated by B-cell lymphoma 2 (Bcl-2) family proteins (13, 14). 

The activation of any of these pathways induces a cascade of caspases (a family of protease enzymes acting as initiator or effector molecules of apoptosis), such as CASP3, CASP6, and CASP7, resulting in cell death. NF-κB, JAK-STAT3, and MAPK signaling pathways are other apoptotic signaling pathways. However, these pathways are often defective in cancer-initiating cells, thus further inhibiting cell death, which in turn leads to the occurrence of tumors (12, 15).

Researchers posit that regulating the apoptosis signaling pathway to induce apoptosis in cancer cells and limit the death of normal cells is a promising approach to treating cancer (16, 17). Some researchers also suggest  targeting two or more regulated cell death pathways may be beneficial for treating cancer (12).

Replicative immortality

A core biological characteristic of cancer cells is their ability to proliferate infinitely, enabled primarily by constantly renewed telomeres, DNA–protein structures at the ends of chromosomes that protect against chromosomal degradation and maintain chromosomal stability (18).

In normal physiology, as cells divide, the telomeres shorten. This process continues until the telomeres become so short that the cell stops dividing (senescence) and dies (crisis) (19). Hence, telomere length may work as a biological clock that tells a cell’s lifespan (20).  Limitless proliferation and tumor formation are impossible as this senescence and crisis process stops older cells more likely to mutate from continuing to divide (21, 22). However, the presence of telomerase in tumor cells allows them to survive beyond their lifespan.

Telomerase is an enzyme that prevents telomeres from reaching a limit that triggers senescence and crisis by adding telomere repeat sequences to the chromosome ends (23, 1). It is absent in normal cells but highly expressed in 85 to 90% of cancer cells. Hence telomerase inhibitors may be relevant as cancer therapeutics. Imetelstat, a telomerase inhibitor, is being studied for treating myelofibrosis (MF), a blood cancer (24).

Inducing angiogenesis

Dysregulated signaling pathways, including VEGF and PDGF pathways, in cancer cells, enable abnormal blood vessel formation that supplies oxygen and nutrients to tumors and removes waste. In normal physiology, angiogenesis is a tightly regulated blood vessel formation process that only occurs when and where needed and is necessary for vital functions such as wound healing, menstrual cycle, tissue repair, and muscle growth (25).

In cancer, tumor-progression events such as certain genetic alterations of tumor cells, recruitment of immune cells, and tumor-associated inflammation may trigger an angiogenic switch (26). This causes an imbalance in angiogenic modulators that favors pro-angiogenic factors over anti-angiogenic ones, supporting cancer stem cell function, tumor formation, growth, and spread to other sites, and potential drug resistance (27).

In particular, the VEGF signaling pathway, a positive regulator of angiogenesis, may support angiogenesis in cancer cells when upregulated primarily in response to hypoxia in the tumor or the tumor microenvironment via the activation of transcription factor HIF-1. VEGF may also be upregulated by growth factors such as PDGF and oncogene expression (28, 29).

The cessation of angiogenesis can stop tumor growth and potentially lead to tumor cell shrinkage and death. Thus, researchers recognize VEGF and other signaling pathways involved in pathological angiogenesis as valid therapeutic targets in treating cancer. VEGF inhibitors such as bevacizumab, sunitinib, sorafenib, cabozantinib, pazopanib, regorafenib, lenvatinib, axitinib, and motesanib have been FDA-approved for different cancers (27, 30).

Activating invasion and metastasis

Cancer cells can invade and spread to nearby and distant tissues from their primary site, another feature that sets them apart from normal cells. Cancer metastasis is a prominent reason treatments stop working. It is responsible for the growth of secondary tumors and over 90% of patient deaths and has limited treatment options. Hence, identifying mechanisms and pathways involved in invasion and metastasis may advance more efficient cancer treatments (31, 32).

Cancer cells go through a multi-step process to metastasize, including:

• Migrating from their primary site to invade nearby tissues.
• Entering and circulating in the bloodstream.
• Withstanding shear stress in blood vessels.
• Adjusting to the cellular environment at the secondary site.
• Evading immune defenses (32)

These steps are driven by signaling pathways, including β-catenin/ZEB1, uPA, PI3K/AKT, NF-κB, CXCL12/CXCR4, FAK, and TGF-β. Targeting these priority signaling pathways to disrupt invasion and metastasis is recognized as a potential approach for developing new treatments.

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