1 INTRODUCTION TO CANCER BIOLOGY
1.1 WHAT IS CANCER?
The history of the term cancer starts in 460-370 BC. Earlier the word carcinos and carcinomas were used by the Greek physician Hippocrates to describe non-ulcer forming and ulcer-forming tumors1; these words refers to a crab due to the resemblance of dissected tumor surface with its finger-like prolongation to the veins. Later the term cancer was used by The Roman physician Celsus (28-50 BC) which is the translation of a crab from Latin.
Cancer, in a simple way, can be defined as complex disease in which cells grow abnormally and in an uncontrolled way. As cells grow, massive collection of cells organizes themselves forming tumors. Cancerous tumors are able to disseminate to the distant organs unlike benign tumors which do not spread around. This behavior is a result of some modifications of genetic information that alter cell functions. There are various risk factors that cause these changes; they can operate in a consecutive order or simultaneously.
Aging, alcohol use, exposure to cancerous substances, chronic inflammation, diet, hormones, immunosuppression, infectious agents, obesity, radiation, sunlight and tobacco are the most-studied known or suspected risk factors2.
However, to understand how these risk factors can generate cancer, underlying mechanisms of cancer should be revealed. Hanahan, D. and Weinberg, R. A3 have published a very extensive review about what are the acquired biological capabilities that reconstruct normal cell into cancerous cell; ‘‘Hallmarks of Cancer : The Next Generation’’. In this section, the cellular, biochemical and molecular traits of cancer will be discussed.
It had been previously suggested that the process of tumor development for any type of cancer comprises the following common traits: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis (Figure 1). However, taking into account the outcomes of recent researches, there are also two emerging hallmarks:
reprogramming of energy metabolism and evading immune destruction and as well as the importance of the tumor microenvironment 3.
FIGURE 1 : HALLMARKS OF CANCER (IMAGE COPIED FROM REF 3.)
Growth-promoting signals are the key to cell growth-and-division cycle. Their production and release is well-controlled by normal cells. These signals act when the growth factors bind on the cell surface receptors initiating some cellular signaling pathways and regulating the cell cycle with the influence of cell survival and energy mechanism. However cancer cells can deregulate these signals leading to acquire sustained proliferative capability. There might be several ways of gaining this trait: growth factor ligands can be produced by the cells itself or normal cells can be stimulated by the cancer cells to supply with various growth factors. These aberrations in growth factors could be the results of somatic mutations that activate downstream pathways or defects in the negative-feedback mechanism that reduces various signaling leading to enhanced proliferation.
Normal tissue growth is also controlled by the anti-proliferative signals operating to downregulate the cell proliferation; which are coded by tumor suppressor genes. Escaping these pathways is another hallmark capability of cancer. For example, p53 protein is encoded by TP53 tumor suppressor gene and has an significant role on cell cycle arrest, DNA repair and apoptosis4. Mutation of this gene may cause loss of function, promote other tumorigenic pathways or exhibit oncogenic activity by a gain-of function mechanism5 which results in increased proliferation, evasion of apoptosis and chemoresistance6,7.
Defects in cell growth and proliferation are normally circumvented by the natural protection mechanism called apoptosis, programmed cell death. Apoptosis is activated by the loss of cell-cycle checkpoints, persistent DNA damage, or malfunction of telomerase8. Extra-cellular death-inducing signals and cell intrinsic signals are the main decisive components in this process in which pro and antiapoptotic regulatory proteins are counter-balancing each
other9. Nevertheless, cancer cells gain resistance to apoptosis to persist their malignant growth. One common way, as mentioned earlier, is through the lack of p53 protein which activates the apoptotic process10.
Another acquired hallmark for cancer cells is having unlimited replicative potential. Under the normal conditions, cells have a limited number of growth and division cycles due to two phenomena, senescence and crisis. Having a finite number of dividing, cell stop growing and it resides in a viable but nonproliferative state which is senescence; thereafter, cells surviving this state die massively, which is the phenomenon called crisis. Therefore to generate massive tumors, cells have to evade these programs and multiply limitlessly.
According to the studies, telomeres are part of the process to gain unlimited proliferation skill11. Telomeres protect the end of the chromosomal DNA and as cell proliferate they get shorten leading to disability of chromosomes which later induce the crisis state. For example, the activity of telomerase, the enzyme that creates telomere segments, has been found increased in the immortalizing cells extending the telomeric DNA, and thereby replicative proliferation.
As the tumor grows massively, this complex tissue needs to be well supplied with nutrients and oxygen and this is maintained by the tumor-associated neovasculature generated by angiogenesis. During the development of the body, vasculature is generated by the proliferation and differentiation of endothelial cells into a vascular tissue and their assembly into the tubular network and additionally the sprouting of the new vessels from existing ones thereafter the maturation of the network12. The process angiogenesis stays generally quiescent. However, on the contrary, during the tumor progression, angiogenesis induction is kept activated in order to feed the tumor continuously and sustain the cancer growth.
Angiogenic switch is established by the balance between pro-angiogenic and anti-angiogenic molecules. For example, VEGF (vascular endothelial growth factor) is one of the regulatory factors often highly expressed in many of cancer in which it acts on producing new blood vessels, thus helping to nourish the tumor cells13. Hence inducing angiogenesis is a hallmark of cancer contributing the tumor progression.
Many cancer types eventually activate invasion and metastasis at distant organs. Metastasis is a multi-stage process in which the cells gain motility properties, escape from their primary site and reenter into the distant tissues through blood stream and growth of small cancer nodules (colonization) into a new body parts. Nevertheless some cancers types may not able to metastasize due to the lack of the other described hallmarks and fail to advance in one of the steps of the process. Some elements of those steps of metastasis mechanism are yet to be discovered. Cancer cells exhibit typical characteristics during this process such as cell shape alterations, loss of their attachment to the other cells and to
the extracellular matrix (ECM) to enhance their mobility and migration to leave into the blood stream. Another important criterion during metastatic process is the host environment in which the cancer cells has to adapt successfully to colonize; some tissues may be more prone to form metastasis facilitating their acquiring hallmark and growth further. The details of metastatic process will be further discussed in the next sections.
All these hallmarks, briefly described, are what cancer acquires as functional capabilities to survive, grow and spread during the progression of the disease. However, these abilities are acquired thanks to two other enabling characteristics, genome instability and mutations and tumor-promoting inflammation. Modifications in genome help to favor selectively the growth of aggressive clonal subclasses through various mechanisms. Now there is increasing evidence that inflammation generated by infiltrated immune cells within tumors can promote tumor progression for instance by supplying bioactive molecules to the microenvironment inducing proliferation, invasion, angiogenesis or release of mutagenic chemicals from inflammatory cells14.
Apart from those enabling characteristics, two other features of cancer are now considered as emerging hallmarks, in which more evidences are needed to be identified as core hallmark: deregulating cellular energetics and avoiding immune destruction. Energy metabolism and glucose uptake is reprogrammed in cancer cells due to the lower efficiency of energy production and this was observed in many cancer types. Lastly, according to the observations, it is suggested that cancer cell may circumvent immune eradicating system by disabling some of its components that manage to eliminate them.
All in all, in this section, acquired capabilities and enabling factors of cancer have been described briefly. However, there are still numerous key points of tumor progression mechanisms waiting to be discovered and need to be interconnected. Moreover, each of these hallmarks is a potential target for cancer treatment. Especially considering the fact that cancer cells can possess more than one capability at the same time, deactivating several of these traits will substantially increase the efficacy of treatment. An example for combining treatment approaches is to coadminister immunotherapy with chemotherapy regimens. Immunotherapies provide increasing anti-tumor immune response and antagonizing regulatory pathways inducing immune tolerance15. Especially by immunotherapy it is aimed to have more efficient and less toxic cancer treatments.