D. Hanahan and Robert A. Weinberg supposed that the genotype of cancer cells is the manifestation of eight fundamental changes in cellular physiology (The hallmarks of cancer[1], The hallmarks of cancer – The next generation[2]): self-sufficiency in growth signals, insensitivity to antigrowth signals, evading apoptosis, limitless replicative potential, sustained angiogenesis, tissue invasion and metastasis, reprogramming energy metabolism and avoiding immune destruction.
Each of these physiologic changes, new abilities acquired during tumor progression, represents the violation of an anti-cancer defense mechanism wired in normal tissues and cells.
The acquisition of these traits is made possible by two enabling characteristics: the development of genomic instability in cancer cells and the inflammation of pre-malignant and malignant lesions.
Self-Sufficiency in Growth Signals
Normal cells need mitogenic growth signals to switch from quiescence to a proliferative state; cancer cells, on the contrary, show an extremely reduced dependence upon exogenous growth stimulation: they generate autonomously many of their own growth-signals, disrupting an homeostatic mechanism that operates to ensure a correct behavior of the different cells types within a tissue. Cancer cells can also switch the extracellular matrix receptors (the integrins) they express, favoring those who transmit pro-growth signals.
According to various evidence, it’s likely that cell-to-cell growth signaling operates in the vast majority of human cancer, which are all composed by different types of cells that communicate through heterotypic signaling: cancer cells are successful if they succeed in inducing the nearby normal cells to release pro-growth signals.
Insensitivity to Antigrowth Signals
In normal tissues, multiple anti-proliferative signals operates to maintain cellular quiescence and tissues homeostasis; these signals can block proliferation through two different mechanism: cells can be forced to switch from the proliferative state to the quiescent one, or they can be induced to renounce permanently to their proliferative potential. Pre-cancerous cells must evade this signals if they want to survive.
At the molecular level, maybe all anti-proliferative signals are channeled through retinoblastoma protein (pRb), that blocks proliferation when in a hypophosphorylated state. Disruption of the pRb pathway renders cells insensitive to antigrowth factors.
Furthermore, cancer cells can turn off the expression of integrins, limiting anti-growth signals and favoring instead molecules that send pro-growth signals.
Evading Apoptosis
During apoptosis (programmed cell death), cellular membranes are destroyed, the cytosol is extruded, the nucleus is fragmented and the chromosomes are degraded: the dead cell is engulfed by nearby cells and it disappears.
The biopsy of different stages in human carcinogenesis shows that cancer cells acquire resistance against apoptosis, using different methods: the most important is surely the loss of the pro-apoptotic regulator p53, a tumor suppressor gene, with the consequent inactivation of its product, the p53 protein; this, in turn, causes the removal of a key component of the DNA damage sensor that induce apoptosis.
Limitless Replicative Potential
All cells carry an intrinsic program that limits their multiplication: normally, after they progress through a certain number of division, they stop growing, entering into a senescence state. However, some cells can bypass senescence, disabling some tumor-suppressor proteins, and can continue to replicate for additional generations, until they reach the crisis state. This state is characterized by massive cell death, chromosomes fusions and occasional appearances of a variant cell (1 out of 107) that acquires the capability of limitless replication (immortalization).
Many cancer cells seem to be immortalized: during tumor progression, pre-malignant cells exhaust allowed doublings and can develop their hallmarks capabilities only by reaching immortalization.
The counting device of cells generations is represented by the ends of chromosomes, telomeres: at the end of each cellular cycle, telomeric DNA loses 50-100 bp. The progressive shortening of telomeres eventually causes their inability to protect the end of chromosomal DNA, which hence participates in the fusion with the other chromosomal ends, leading to cells death.
On the contrary, almost all types of cancer maintain telomeres by upregulate expression of the telomerase enzyme or by starting recombination-based interchromosomal exchanges of sequence information.
Sustained Angiogenesis
Cell survival is based upon the oxygen and nutrients supplied by the vasculature: cells are obliged to reside within 100 μm of a capillary blood vessel: at first, this closeness is ensured by the coordinated growth of vasculature and parenchyma, and then angiogenesis is regulated minutely.
Vascular endothelial growth factors (VEGF) and acidic and basic fibroblast growth factors (FGF1/2) initializes angiogenesis, while integrins signals contribute to this regulator balance.
In order to progress, incipient tumor must develop angiogenic ability, changing the balance between angiogenic inducers and inhibitors, often through alteration in gene transcription; however, some evidence suggests that different cells use diverse molecular strategies to activate angiogenesis, making research really difficult.
Tissue Invasion and Metastasis
During cancer progression, primary tumor masses produce pioneer cells that invade nearby tissues, where space and nutrients are not limiting, and base new settlement, the metastasis, that cause 90% of human cancer deaths. These metastasis arise as amalgams of cancer cells and normal supporting cells conscripted from the host tissue.
Invasion and metastasis are two exceedingly complex and closely connected processes, that use similar operational strategies, involving changes in the physical coupling of cells to their microenvironment and activation of extracellular proteases: different proteins involved in cell-to-environment tethering, such as cell-cell adhesion molecules (CAMs) and integrins, are altered in cells with invasive or metastatic abilities.
Reprogramming Energy Metabolism
Under aerobic conditions, normal cells process glucose, first to pyruvate via glycolysis in the cytosol and thereafter to CO2 in the mitochondria; under anaerobic conditions, glycolysis is favored and relatively little pyruvate is dispatched to the oxygen-consuming mitochondria.
It seems that even in the presence of oxygen, cancer cells reprogram their glucose metabolism to promote glycolysis (aerobic glycolysis), by upregulating glucose transporter, maybe in order to facilitate macromolecules and organelles biosynthesis for assembling new cells.
Avoiding Immune Destruction
The theory of immune surveillance proposes that the immune system continuously monitors cells and tissues to recognize and eliminate incipient tumors: following this rationale, solid tumor that do appear have managed to avoid destruction.
In immunecompetent subjects, immunogenic cancer cells are routinely eliminated, leaving only weakly variants that can colonize both immunedeficient and immunecompetent hosts; on the contrary, if this type of cells grows in immunedeficient subjects, the immune system does not eliminate them, and if they are transplanted into syngeneic recipients, they are rejected when they confront, for the first time, the competent immune systems of their secondary hosts.
Recently, an increasing body of evidence suggests that the immune system operates as a barrier to tumor formation and progression, at least in some forms of non-virus induced cancer.
Enabling characteristics:
Tumor-Promoting Inflammation
Nowadays it is clear that every neoplastic lesion contains immune cells at different densities. Historically, it was thought that these cells were an attempt to fight cancer, while by 2000 there are evidence that the tumor-associated inflammatory response paradoxically improves tumor genesis and progression, by providing bioactive molecules to the tumor microenvironment. Moreover, inflammatory cells can release chemicals, actively mutagenic for nearby cancer cells, accelerating their genetic evolution toward malignancy.
Genome Instability and Mutation
The acquisition of hallmark capabilities depends on how alterations in cancer cells genome proceed: mutant genotypes confer selective advantages to sub-clonal cells, leading to their dominance in local tissue environment.
During tumor progression, cancer cells often increase mutation rate by amplifying their sensibility to mutagenic agents or by disrupting the function of one or several components of the genomic maintenance machinery; among these, the most important one is TP53: it activates the retrieval of damaged DNA, blocks cell cycle and induces senescence or apoptosis if the damage is irreparable. Also the loss of telomeric DNA generates karyotypic disorder, depicting telomerase as an essential caretaker of genome integrity.
Importantly, the recurrence of specific aberrations at particular sites in the genome indicates that such sites harbor genes whose alteration favors neoplastic progression.
Figure
How we Fight Cancer Today
Surgery
Surgery is the oldest form of cancer treatment. Advances in surgical techniques have allowed surgeons to operate on a growing number of patients and have good outcomes. When a surgeon has to cut into the body to operate, it is called invasive surgery. Today, operations that involve less cutting and damage to nearby organs and tissues (less invasive surgery) often can be done to remove tumors while saving as much normal tissue and function as possible.
Surgery offers the greatest chance for cure for many types of cancer, especially those that have not spread to other parts of the body. Most people with cancer will have some type of surgery.
Surgery can be done for many reasons. Some types of surgery are very minor and may be called procedures, while others are much bigger operations.
The more common types of cancer surgeries are:
preventive-prophylactic surgery, to remove body tissue that is likely to become cancer, even though there are no signs of cancer at the time of the surgery;
diagnostic surgery, to find out how much cancer there is and how far it has spread;
staging surgery, to find out how much cancer there is and how far it has spread;
curative surgery, when a tumor is found in only one area, and it is likely that all of the tumor can be removed;
debulking-cytoreductive surgery, to remove some of the tumor when removing all of it would cause too much damage to an organ or nearby tissues;
palliative surgery, to treat problems caused by advanced cancer and to reduce patient’s pain;
supportive surgery, to help with other types of treatment;
restorative-reconstructive surgery, to improve the way a person looks after major cancer surgery, or to restore the function of an organ or body part after surgery.
Chemotherapy
Chemotherapy is the use of strong drugs to treat cancer. There are more than 100 chemo drugs used today. Doctors choose certain types of drugs based on the stage of cancer growth. Chemo can be used for different reasons: to keep the cancer from spreading, to slow the cancer’s growth, to kill cancer cells that may have spread to other parts of the body, to relieve symptoms caused by cancer or to cure it.
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Chemo is often used to fight cancers that have spread to other parts of the body (metastasized), and it works to kill any cell that is growing fast, whether it’s a cancer cell or not. So, some of the normal, healthy cells that grow quickly can be damaged. This can cause side effects, but some people have no side effects at all; for most people, side effects will go away in time after their treatment ends. How long that will take is different for each person. Some side effects can take longer to go away than others or they might not go away at all.
The most common ones are nausea and vomiting, hair loss, bone marrow changes, mouth and skin, memory or emotional changes, fertility problems, but they could be prevented or reduced in part.
Radiation Therapy
Radiation therapy uses high-energy radiation to kill cancer cells by damaging their DNA, but it can also damage normal cells. Therefore, treatment must be carefully planned to minimize side effects.
The radiation used for cancer treatment may come from a machine outside the body, or it may come from radioactive material placed in the body near tumor cells or injected into the bloodstream.
A patient may receive radiation therapy before, during, or after surgery, depending on the type of cancer being treated. Some patients receive radiation therapy alone, and some receive radiation therapy in combination with chemotherapy.Computed Tomography Scanner
Linear Accelerator Used for External-beam Radiation Therapy
CT scans are often used in treatment planning for radiation therapy.
During CT scanning, pictures of the inside of the body are created by a computer linked to an x-ray machine.
Many types of external-beam radiation therapy are delivered using a machine called a linear accelerator (also called a LINAC). A LINAC uses electricity to form a stream of fast-moving subatomic particles. This creates high-energy radiation that may be used to treat cancer.
Side effects vary from person to person and depend on the radiation dose and the part of the body being treated. The most common early side effects are fatigue (feeling tired) and skin changes. Other early side effects usually are hair loss and mouth problems.
Cryosurgery
Cryosurgery is a technique for freezing and killing abnormal cells using the extreme cold produced by liquid nitrogen or argon gas. It is used to treat some kinds of cancer and some precancerous or noncancerous conditions, and can be used both on the skin and inside the body, thanks to an instrument called “cryoprobe”, which is guided through ultrasound (creating a picture called “sonogram”) or MRI and placed in contact with the tumor. After cryosurgery, the frozen tissue thaws and is either naturally absorbed by the body (for internal tumors), or it dissolves and forms a scab (for external tumors).
Cryosurgery offers advantages over other methods of cancer treatment: it is less invasive than surgery, involving only a small incision or insertion of the cryoprobe through the skin. Consequently, pain, bleeding, and other complications of surgery are minimized. It is also less expensive than other treatments and requires shorter recovery time, but it has some side effects (although they may be less severe than those associated with surgery or radiation therapy) that depend on the location of the tumor. It can cause cramping, pain, or bleeding, or scarring and swelling; if nerves are damaged, loss of sensation may occur, and, rarely, it may cause a loss of pigmentation and loss of hair in the treated area.
Cryosurgery may offer an option for treating cancers that are considered inoperable or that do not respond to standard treatments. Furthermore, it can be used for patients who are not good candidates for conventional surgery because of their age or other medical conditions.
The major disadvantage of cryosurgery is the uncertainty surrounding its long-term effectiveness: additional studies are needed to determine the effectiveness of cryosurgery in controlling cancer and improving survival.
Chapter II
Nano-Science:
a Chance Against Cancer
The New Challenge of the 21st Century
Nowadays, the scientific and technological challenge is to move from models built from phenomenological description of cancer to network models derived from systems biology, and to transform them in a clinically relevant framework, following and understanding the evolution of the disease. To handle this challenge, both diagnostic and therapeutic technologies and strategies with fewer toxic side effects and more beneficial behavior have to be developed.
Many steps toward this goal have already been made: for example, few years ago we only used some drugs because they seemed to work, even if the mechanism was not well understood (and this often led to undesirable side effects), while today many proposed nanodrugs work by well-understood and very specific mechanisms, and this allows science to revolutionize its methods and its base concepts.
At first, the static model of cancer (figure 4-a) has been substituted by cancer pathways (figure 4-b), following the idea that a given type of cancer can be triggered by different genetic mutations, each leading to a different outcome; then, also this model has been recognized as limited, since it requires a prior knowledge that cancer exists (so it doesn’t represent a good early detection strategy) and it assumes that a given cancer is homogeneous (which is almost certainly incorrect); nowadays, network models (figure 4-c) have been developed to account the real degree of interconnection among the various genes and proteins which formed the cancer pathways: using deep transcriptome analyses, together with focused proteomic investigations, network models allow scientists to understand the patho-physiology of disease progression at the molecular level and then to develop more informative diagnoses; finally, in the near future, the best cancer model will be the dynamic ones, and the evolving picture of cancer will change both diagnostically (thanks to multiparameter, inexpensive measurement and compu-tational technologies) and therapeutically (with the help of new nanotechnologies for drug encapsulation and delivery).
Figure 4New Technologies Against Cancer:
Biomedical Applications
Biomedical Applications
Drugs
Drug delivery
Photodynamic therapy
Molecular motors
Neuro-electronic interfaces
Protein engineering
Nano-luminescent tags
Drugs
At first we need to define the term “Bioavailability”: it is used by several branches of scientific study to describe the way chemicals are absorbed by humans and other animals. Examining a substance’s bioavailability in pharmacological studies helps to determine dosages of particular medications through aspects like absorbency and half-life, so it can evaluate medication.
As regards nanotechnologies, they are really important to develop entirely new methods to increase bioavailability, controlling drug delivery in several ways:
One of the biggest problem of drug delivery is that of making possible for polar drugs to pass the non-polar membranes of the cancerous cells and to act directly within them, where the main process which originates the disease takes place. A solution to this problem could be that of encapsulating the polar drugs in non-polar coating such as cholesterol or liposome structures based on balls of fatty molecules: these molecules can pass the membrane and allow the drugs to combine with alien pathogenic DNAs preventing the mitosis of the cancerous cells.
Drug molecules can be encapsulated in polymeric structures which open within the body when they are need: in this way it is possible to create time-released drugs depending on the “consistence” of these polymeric structures. Solid drugs can be also grind into fine powders to expand the surface area and the reactivity of the interested zone and to increase drugs solubility within the body.
Intravenous administrations of medications are considered to have 100% bioavailability because they do not pass through the stomach. They are immediately in the circulatory system. However, other medications administered at the same time may reduce the effects of an intravenous administration and affect its bioavailability.
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