Cancers on the molecular level in biology

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A generic term cancer used to describe as many as 200 malignant diseases which occur in various tissues and cause variety of illnesses. Types of cancer known are almost equal to type of cells present in body. Regarding spread, incidence, and survival rates, each cancer has its own characteristics, however they share one common characteristic; that there is uncontrolled malignant cell division, generally from a single primary site (1).

There are twenty three pairs of chromosomes present in every normal cell of human body. DNA is responsible for controlling and transmitting genetic characteristics in the chromosomes, we inherit from our parents and pass on to our children. Genes are subunit of chromosomes, single chromosome contain millions of different genes. These genes contain information on how the body should function, behave and grow. Genes determine the various aspects of the body, like colour of eyes, healing of injured tissues, secretion of gastric juice and many more. During normal condition these genes function properly and send the correct messages. As the chromosome reproduces itself, it is resulted in a cell division. Therefore there are number of opportunities for something to go wrong.

Genetic change or damage to the chromosome within the cell resulted in cancer. Alteration in genes, leads to sending improper or wrong messages or entirely different message from one it should give. This improper signaling further leads to rapid growth of cell. Further multiplication of cell occurs again and again until it forms lump, that's called tumor, malignant or cancer (2).

Generally as cancer grows in a body, it is discovered, either by a patient himself/herself as an ill feeling, or as a suspicious lump, or, more often now a days by medical practitioner in a regular diagnostic test or a standard screening like mammography.

During diagnosis and treatment of patient with cancer, imaging investigation plays an essential role. Imaging techniques are not just used for initial diagnosis but it contributes a significant part in monitoring the effectiveness of treatment. Main aim of molecular imaging is to show fine structures within the patient without need of surgical investigation (3).

Molecular imaging

Since the first microscope was built in the late sixteenth century, morphological observations have driven the course of biology (4). In early twenty first century a new discipline emerged which is intersection of molecular biology and in vivo imaging and referred as molecular imaging. Molecular imaging may refers to the combination of approaches from various disciplines like chemistry, pharmacology, physics, engineering, bioinformatics, cell and molecular biology. Major application of molecular imaging is to evaluate the specific process at the cellular and sub cellular levels in living organisms (5).

Molecular imaging has enormous potential as a powerful means to monitor and diagnose a disease by mapping the anatomic locations of specific molecules of interest within living tissue (6). Imaging can provide the potential for understanding of earlier detection and characterization of disease, integrative biology and evaluation of treatment.

Molecular imaging and cancer

Tissue sampling is one of the most common methods used for represent the biochemical or pathological process under investigation; however it may not always adequate because of tissue heterogeneity, which is especially characteristic of some tumors (7). Today with the help of molecular imaging technique, clinicians are able to see not only where a tumor is located in the body, but also to visualize biological processes (apoptosis, metastasis and angiogenesis), expression and activity of specific molecules (protease and protein kinase) that influence tumor behavior and/or response to therapy. This information have great role in drug development, individualized treatment cancer detection as well as our understanding of how cancer arises (8). Moreover, the newly developed techniques in molecular imaging allow quantification and visualization of clinically relevant physiological variables such as oxygen consumption, blood flow, proliferative activities, glucose metabolism and tissue hypoxia as they takes place in living cells an tissues.

Furthermore, one can potentially identified molecular pathways, tumor specific receptors and altered gene products with the help of molecular imaging. It will effectively be possible to estimate at risk patients earlier pathogenesis, perhaps before a tumor has even had a chance to become malignant. For detection and elucidation of disease prognosis at microscopic level, techniques such as optical imaging hold particular promise (9).

During all phases of cancer management, starts from prediction, screening, biopsy guidance for detection, staging, prognosis, therapy planning therapy guidance, therapy response, till recurrence and palliation biomedical imaging plays a crucial role. Biomarkers which are identified from the proteome and genome can be targeted using chemistry that selectively binds to the biomarkers and amplifies their imaging signal (10).

Current role of imaging in cancer management

(Molecular oncology, (2008) 115-152

In cancer management, molecular imaging of prolification, metabolism, and other more specific targets may therefore be of additional value. As mentioned above, molecular imaging is emerging field, for this purpose ligands can be labeled with either a fluorescent dye for optical imaging, contrast agent for magnetic resonance imaging (MRI), gamma emitting radionuclide for single photon emission computed tomography (SPECT) imaging or a positron emitting radionuclide for positron emission tomography (PET) (11).

Moreover, number of different techniques like X-ray imaging (mammography and X-ray CT), ultrasound imaging (colour doppler imaging), and nuclear medicine (gamma camera, positron emission tomography and intra-operative probes) are used for molecular imaging of cancer (12).

Molecular imaging in combination with structural and functional imaging is fundamental to achieve gene expression and molecular processes within cells and tissues. Wide variety of targeted agents for cancer markers including avb3 integrin, vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR) receptors, carcinoembryonic antigen (CEA), , MC-1 receptor, somatostatin receptors, prostate stimulating membrane antigen (PSMA), transferrin receptors and folate receptors have been developed.

Except ultrasound which is based on the reflection, scattering, and frequency shift of acoustic waves, most clinical imaging systems are based on the interaction of electromagnetic radiation with body tissues and fluids.

Non-ionizing electromagnetic radiation imaging techniques such as electrical impedance spectroscopy, infrared spectroscopy and tomography, photoacoustic and thermoacoustic imaging and microwave imaging spectroscopy have been investigated mainly for breast imaging.

Future role of molecular imaging

Molecular oncology, (2008) 115-152

Nuclear medicine and positron emission tomography (PET) are the most sensitive clinical imaging techniques with between nanomole/kilogram and picomole/kilogram sensitivity. MR has about 10 mmol/kg sensitivity whereas X-ray systems including CT have millimole/kilogram sensitivity.

In cancer research institutes preclinical fluorescence and bioluminescence-based optical imaging systems are in routine use. Nanoparticals targeted tumor biomarkers and Raman spectroscopy are showing promise for future development (10).

Molecular oncology, (2008) 115-152

Application

The major motive of molecular imaging techniques is to assess specific processes at the cellular level, including gene expression, dynamic cell tracking throughout the entire organism, protein-protein interaction and drug action analysis in living cell or tissue. Molecular imaging contributes a key role in understanding of the physiology of living organisms and offer new means for drug target identification and pre-clinical testing to improve drug discovery. These goals can be achieved rapidly, non-invasively, quantitatively, and repetitively in the same animal, under different conditions and stimuli with the help of molecular imaging (13).

For breast cancer molecular imaging can potentially be used for screening, staging, restaging, response evaluation and guiding therapies. Optical imaging, single photon emission computed tomography (SPECT) or radionuclide imaging with positron emission tomography (PET) and magnetic resonance imaging (MRI) are the major techniques used for molecular breast cancer imaging. Several tumor characteristics are candidates for development of tumor specific tracers in case of breast cancer imaging.

Schematic presentation of the potential targets for breast cancer molecular imaging

T.H. Oude Munnink et al. / The Breast 18 (2009) S66-S73

DNA synthesis or tumor cell glucose metabolism is higher in tumor cell as compared to normal cells, and by targeting these general phenomena one can visualize the tumor cell. For visualization of glucose metabolism in tumor cell, [18F] fluorodeoxyglucose (FDG) is most used PET-tracer. FDG is phosphorylated by hexokinases to FDG-6-phosphatase after transported across the cell membrane by glucose transporter proteins. Unlike glucose-6-phosphate, FDG-6-phosphate lacks a hydroxyl group at the 2-position, and therefore it is not further metabolized and thus 'trapped' in the cell. This leads to accumulation of FDG in tumor cell, which is regulated by the activity of the glucose transporters and hexokinase. In 45-90 minutes after injecting FDG into body, the tumor uptake can be detected with a PET camera (14).

Moreover, expression of hormone receptors in tumor cell is found in most of the breast cancer, and these receptors are interesting targets for imaging in these subsets of patients. During diagnosis of breast cancer, 70% of patients have tumors positive for hormone receptors, of which the majority are positive for estrogen receptor (ER). The PET tracer 16-a-[18F] fluoro-17-b-estradiol (FES) was used as a receptor ligand for ER that binds to both subtypes ERa and ERb, with a preference for ERa (15).

Furthermore, receptors present at tumor cell membrane, such as Insulin-like Growth Factor-1 Receptor (IGF-1R), Epidermal Growth Factor Receptor (EGFR), Platelet Derived Growth Factor b Receptor (PDGF-bR), and Human Epidermal growth factor Receptor 2 (HER2) may be of interest for imaging. Additionally, expression of growth factors by tumor cells like Transforming Growth Factor b (TGF-b) and Endothelial Growth Factor (VEGF) in tumor microenvironment and therefore are tracer target candidates.

In around 25-30% of breast cancer patients, it is found that there is overexpression of HER2 due to HER2 gene amplification. Fab-fragments, F(ab_)2-fragments, full length monoclonal antibodies, minibodies, diabodies, affibodies and peptides are currently available HER2 targeted ligands (16,17).

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