Signal Transduction in Cancer
The cells of our bodies are also constantly receiving signals from other cells, as well as living organisms are constantly receiving signals from our environment. These signals are important to keep cells alive and functioning to stimulate important events (such as cell division and differentiation). Signal transduction is the process by which a chemical or physical signal is transmitted through a cell.
Cancer refers to any one of a large number of diseases characterized by the development of abnormal cells that divide uncontrollably and have the ability to infiltrate and destroy normal body tissue. As the figure 1 shows, most cancers arise in epithelial cells (especially solid tumors), manifesting as carcinomas in organs such as the lung, skin, breast, liver, and pancreas. After a tumor expands, the tumor core loses access to oxygen and nutrients, leading to the growth of new blood vessels (angiogenesis), which restores access to nutrients and oxygen. Subsequently, tumor cells can develop the ability to invade the tissue beyond their normal boundaries, enter the circulation, and seed new tumors at other locations (metastasis), the defining feature of malignancy.
Figure 1. Cancer progression
*this diagram is derived from publication on Cold Spring Harb Perspect Med [1]
The development of cancer involves successive genetic and epigenetic alterations. Successive genetic alterations cause to abnormal signaling transduction. The common signaling pathways involved in cancer are as follows:
- Wnt signaling pathway: The Wnt signaling pathway is critically involved in both the development and homeostasis of tissues via regulation of their endogenous stem cells. Aberrant Wnt signaling has been described as a key player in the initiation of and/or maintenance and development of many cancers, via affecting the behavior of Cancer Stem Cells (CSCs) [2]. The Wnt pathway is commonly divided into β-catenin dependent (canonical) and independent (non-canonical) signaling [3]. And non-canonical signaling can be further divided into non-canonical planar cell polarity (PCP) pathway and non-canonical Wnt/calcium pathway. Interesting reading about Wnt signaling pathway...
- Hedgehog (Hh) signaling pathway: The Hedgehog (Hh) signaling pathway is highly conserved from flies to humans. It is essential for normal embryonic development and may be aberrantly activated in a wide variety of human cancers [4] [5]. In mammals, Hh signaling regulates both patterning and polarity events during early embryogenesis and the morphogenesis of specific organs and tissues. The pathway is subsequently silenced in most adult tissues but can be reactivated following injury to promote repair and regeneration [6].
- Tyrosine Kinase Receptor Pathways: Receptor tyrosine kinases (RTKs) are a subclass of tyrosine kinases that play an important role in a variety of cellular processes, including cell growth, motility, differentiation, and metabolism. Currently, there are 58 known RTKs in humans, such as EGFR, HER2/ErbB2, and MET. Abnormal RTK activation in human leads to an assortment of human diseases. Among of these diseases, cancer is the most notably and usually caused by four principal mechanisms: gain-of-function mutations, genomic amplification, chromosomal rearrangements, and / or autocrine activation [7] [8].
- Transforming growth factor-β pathway: Transforming growth factor-beta (TGF-β) signaling is one of the important cellular pathways that play key roles for tissue maintenance. In particular, it is important in the context of inflammation and tumorigenesis by modulating cell growth, differentiation, apoptosis, and homeostasis [9]. In an advanced tumor, TGF-β signaling pathway induces tumor invasion and metastasis through promoting angiogenesis, epithelial-mesenchymal transition, and immune escape [10]. Interesting reading about transforming growth factor-β pathway…
- Nuclear factor-KB signaling pathway: Nuclear factor-κB (NF-κB) transcription factors and the signalling pathways that activate them are central coordinators of innate and adaptive immune responses [11]. There are two pathways for NF-kB activation, as the canonical and non-canonical pathways, which require complex molecular interactions with adapter proteins and phosphorylation and ubiquitinase enzymes [12]. More recently, it has become clear that NF-κB signaling also has a critical role in cancer development and progression. NF-κB provides a mechanistic link between inflammation and cancer, and is a major factor controlling the ability of both pre-neoplastic and malignant cells to resist apoptosis-based tumour-surveillance mechanisms
References
[1] Sever R, Brugge JS. Signal transduction in cancer [J]. Cold Spring Harb Perspect Med. 2015, 5(4):a006098.
[2] Yann Duchartre, Yong-Mi Kim, and Michael Kahn. The Wnt Signaling Pathway in Cancer [J]. Crit Rev Oncol Hematol. 2016, 99: 141-149.
[3] Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene [J]. 2017, 36(11):1461-1473.
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[5] Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles [J]. Genes Dev. 2001, 15(23): 3059-87.
[6] McMillan R, Matsui W. Molecular pathways: the hedgehog signaling pathway in cancer [J]. Clin Cancer Res. 2012, 18(18):4883-8.
[7] Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases [J]. Cell. 2010, 141:1117-34.
[8] Zhenfang Du & Christine M. Lovly. Mechanisms of receptor tyrosine kinase activation in cancer [J]. Mol Cancer. 2018, 17, 58.
[9] Itatani Y, Kawada K, Sakai Y. Transforming Growth Factor-β Signaling Pathway in Colorectal Cancer and Its Tumor Microenvironment [J]. Int J Mol Sci. 2019, 20(23):5822.
[10] Chen Y, Di C, Zhang X et al. Transforming growth factor β signaling pathway: A promising therapeutic target for cancer [J]. J Cell Physiol. 2020, 235(3):1903-1914.
[11] Michael Karin. Nuclear factor-κB in cancer development and progression [J]. Nature. 2006, 441, pages431-436.
[12] Mohammad Reza Zinatizadeh, Bettina Schockb, Ghanbar Mahmoodi Chalbatani. The Nuclear Factor Kappa B (NF-kB) signaling in cancer development and immune diseases [J]. Genes & Diseases. 2020.
