Cancer is a leading cause of death worldwide and has become a major public health issue in the developed countries. Cancer development is a multistep process, during which the cells accumulate genetic abnormalities, especially in oncogenes and tumor suppressor genes, contributing to uncontrolled proliferation. These abnormalities provide several growth advantages. Indeed, the transformation from normal cell to tumor cell frequently involves mutations in the cell genome.

Hanahan and Weinberg described six key changes that occur during the transformation from a normal cell to a tumor cell; these features may be considered hallmarks of cancer. These comprise of sustaining proliferative signaling, evading growth suppressors, resisting apoptosis, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, disrupting metabolism, and avoiding immune destruction [1] (Figure 1).

Four additional hallmarks and characteristics have been proposed by Hanahan, and these could be considered as part of the core hallmarks of cancer (Figure 1). More recently it has become evident that the cancer cell-derived extracellular vesicles/exosomes and their molecular cargo are implicated in almost all hallmarks of cancer as critical mediators of inter-cellular communication [1]. It has also been recognized that the tumor microenvironment plays a large critical part in tumorigenesis and malignant progression [2].

Expression of proliferation and survival signals by tumor cells allows them to grow continually as immortalized cells. To achieve growth independent of external growth factors, some tumor cells express activating mutations in proteins involved in cell growth. With a reduced dependence on exogenous growth signals, cancer cells can disrupt homeostasis and rapidly proliferate [3]. For example, ~50% of melanomas bear mutations in the gene coding for the serine-threonine kinase BRAF, and among these, about 90% are V600E point mutations [4].

With the ability to evade growth-inhibiting checkpoints, cancer cells can proliferate rapidly without suppression. Some of the most common tumor suppressants circumvented by cancer cells include signals of p53, retinoblastoma proteins, and transforming growth factor-beta (TGF-β) [5].

Retinoblastoma-associated proteins are responsible for regulating cells through growth-and-division cycles, whereas p53 proteins get signals from stress and abnormality sensors and can either halt cell-cycle progression or trigger apoptosis. In late-stage tumors, TGF-β can be found to activate cellular programs that confer traits to cancer cells associated with high-grade malignancy [1].

Approximately 90% of human cancer deaths are due to metastases, which are caused through invasion of adjacent tissues from the primary tumor site. A complex process, both invasion and metastasis involve utilizing changes in the physical coupling of cells to their environments and activation of extracellular proteases. Cell-cell adhesion molecules (CAMs), such as certain immunoglobulins, cadherins, and integrins, play a critical role in cancer cells invading and metastasizing new sites. E-cadherin is an example of a CAM that frequently observes downregulation and mutational inactivation in carcinomas [1].

A hallmark to many cancers, acquired resistance to apoptosis is a key feature in the survival and growth of cancer cells. Tumor cells limit apoptosis through the loss of p53 function, increased expression of antiapoptotic regulators or survival signals, or by downregulation of proapoptotic factors. This demonstrates that cancer cells operate diverse apoptosis-evading mechanisms during progression to malignancy [1].

Some targets associated in cell death include danger-associated molecular patterns which are released upon cell stress (HSP70, HSP90), HMGB1 in response to anti-cancer therapy and immunogenic cell death, and DKK1 which is secreted to regulate cell survival via the WNT signaling pathway.

Although not fully characterized, evading immunological destruction by T and B lymphocytes, macrophages, and natural killer (NK) cells is considered a new emerging hallmark of cancer. While the immune system acts as a significant barrier to tumor formation, under certain conditions (such as immunodeficient/immunocompromised state), the tumors can form more frequently and grow quicker. Furthermore, immunogenic cells can disable or paralyze T lymphocytes or NK cells—evading the immune system [1].

It has also been noted that certain inflammatory responses (such as infections or wound healing) have the inadvertent effect of supporting tumor functions. For example, inflammation can supply tumor microenvironments with growth and survival factors, and various enzymes that facilitate angiogenesis and aid in invasion and metastasis [1].

Some tumor cells overexpress vascular endothelial growth factor (VEGF), which is a major angiogenic factor. Secretion of angiogenic factors such as VEGF by tumor cells create blood vessels, which provide nutrients to the interior of tumors. These blood vessels are architecturally different from normal blood vessels being less organized. In order to grow, the tumors need to have blood supply to their interior, for delivery of nutrients and O₂. The process of blood vessel growth is called angiogenesis, and most solid tumors secrete angiogenic factors [3].

Cancer cell-derived exosomes have emerged as a novel class of biomarkers playing a significant role in almost all hallmarks of cancer. As crucial mediators of inter-cellular communication, they transfer their molecular cargo from the releasing cell to the recipient cell. Recent advances have particularly focused on cancer cell-derived exosomes that contribute to tumorigenic and metastatic processes. This is achieved by shaping the tumor microenvironment, which is a valuable source of biomarkers in liquid biopsies [6].

Exosomes are secreted by almost all cell types, including cancerous cells. Tumor-derived exosomes have been reportedly involved in cancer malignancy by supporting proliferation, establishing pre-metastatic niches, and regulating drug resistance. They can also assist in the regulation and mediation of organotrophic metastasis, re-education of stromal cells, endocrine/paracrine induction of cancers, angiogenesis activation, immune system modulation, and remodeling of the extracellular matrix [6].

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