CANCER OVERVIEW

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Cancer is a major public health problem in the United States and other developed countries. Approximately  23%  of deaths in the United States were from cancer in 2004, which ranks cancer as second only to heart disease as the most common cause of death ¹. Based on an annual report from the American Cancer Society (ACS), 1.44 million new cancer cases and 560,000 deaths from cancer are expected to occur in the United States in 2007 ¹. While the absolute number of cancer deaths decreased for the second consecutive year in the United States and much progress has been made in reducing mortality rates and improving survival, cancer has still surpassed heart disease as the leading cause of death in the United States in people under the age of 85 since 1999 ².

Cancer is considered a collection of complex genetic and epigenetic diseases characterized by deregulations in molecular signaling that regulate cell growth, survival, proliferation and differentiation. In the past half century, the analysis of human tumor specimens has allowed the identification of many molecules and pathways important for the malignant phenotype. However, we still lack a complete understanding of the events that contribute to the formation of any specific type of cancer. Experimental models of human cancer have shed light on the pathways involved in cell transformation. The in vivo and in vitro studies suggest that combinations of many signaling pathways confer tumorigenicity on human cells and that both tumor-immune systems and tumor-stromal interactions play critical roles in tumor formation and progression.

CANCER BIOLOGY

The adult human body is composed of approximately 10¹⁴ cells, many of which divide and differentiate in order to repopulate organs and tissues. Through a network of molecular signaling mechanisms, the human body maintains the balance between cell proliferation and cell death, thus keeping a constant weight over many decades. Any organ or tissue, so that a detectable neoplasia arises after many cell generations ³. Factor that disrupts this balance potentially alters the total number of cells in particular mutations in the genes which control proliferation, differentiation or apoptosis are responsible for cancer. The majorities of mutations that give rise to cancer are not inherited, but arise spontaneously as a consequence of damages to DNA resulting in altered function of crucial genes.

During the course of tumor progression, cancer cells acquire a number of phenotypic alterations. These include the capacities to proliferate independently of exogenous growth-promoting or growth-inhibitory signals, to invade surrounding tissues and metastasize to distant sites, to elicit an angiogenic response, and to evade mechanisms that limit cell proliferation, such as apoptosis and replicative senescence ⁴. These properties reflect alterations in the cellular signaling pathways that in normal cells control cell proliferation, survival and motility. Many components of these pathways are possible targets for cancer therapy. Pathological analyses of a number of organ sites reveal lesions that appear to represent the intermediate steps in a process through which cells evolve progressively from normalcy via a series of premalignant states into invasive cancers ⁴. Morphological characteristics of premalignant states reflect the genetic changes which occur gradually during the tumorigenesis process.

One of the distinguishing features of cancer is that it grows independently from the restrictions present in normal tissues ⁵. Benign tumors also expand and compress, but do not attack or invade adjacent tissues. Cancer cells ignore the anatomic barriers of adjacent basement membranes and invade through the vascular wall. Upon reaching a circulatory conduit, cancer cells often travel with lymphatic or venous circulation to remote sites where they leave the circulation and colonize in the distant organs, establishing metastases. In the absence of an intervening event, and given enough time, with few exceptions, the cancer process eventually disrupts normal anatomy or function of organs, leading to death.

CANCER THERAPY

Surgery, chemotherapy and radiation therapy are the three major treatment options for most cancer patients. Surgery operates by zero-order kinetics, in which 100% of excised cells are killed and the tumor burden is reduced. In contrast, chemotherapy and radiation therapy operate by first-order kinetics, and only a fraction of tumor cells are killed by each treatment; the successfulness is largely dependent on the sensitivity of the residual disease. As the oldest modality of cancer therapy, surgery still is the mainstay of treatment in solid tumors. Surgery is most effective in the treatment of a localized primary tumor and associated regional lymphatics. Prolonged survival is possible when surgical resection is applied to some metastases in the lung, liver, or brain. For example, a 5-year survival rate between 40% and 70% can be anticipated after surgical resection of solitary colorectal metastasis in the lung and liver ^6,7. With the advent of radiation therapy in the 1910s ⁸ and chemotherapy after the 1940s ⁹, cancer treatment has become more effective with the use of combined modality therapy. With further improvements in operative technique, combined modality therapy has significantly reduced the morbidity and mortality associated with the surgical treatment of solid neoplasm.

Chemotherapy alone or in combination with radiation therapy improves disease-free survival and prolongs quality of life for most cancer patients who have microscopic residual metastases after surgery. Randomized clinical trials have demonstrated the benefit of adjuvant chemotherapy in a variety of tumors, including breast cancer, colon cancer, osteogenic sarcoma, testicular cancer, ovarian cancer, and certain lung cancers. For a few disease entities, such as some germ cell tumors and leukemia, chemotherapy for obvious metastatic disease is curative. Adjuvant chemotherapy after surgery has been demonstrated to be curative in several diseases, including Wilms tumors and osteosarcoma, for which surgery alone or chemotherapy alone has low cure rates. In many other neoplastic diseases, there is evidence of prolonged disease-free survival and of longer survival, such as stage II and III breast cancer, stage III ovarian cancer, and stage III colon cancer ^10-12. Chemotherapy before surgery or induction chemotherapy is beneficial under certain conditions and allows for a reduction in amputations or enhances the effectiveness of radiotherapy.  Tumor cells are heterogeneous and a fraction of them are in G₁ or G₀, presumably because of tumor hypoxia and a low growth fraction, providing a basis for combination chemotherapy ^13,14. Cell cycle-specific agents are employed to kill mitotically active cells, and non-cell cycle-specific agents are added to damage the noncycling tumor cells.

Radiation therapy was developed soon after the discovery of X-rays in 1895.  Radiation randomly interacts with molecules within the cell. Although the critical target for cell killing is deoxyribonucleic acid (DNA) ¹⁵, damage to the cellular and nuclear membranes and other organelles may also be important. Radiation deposition results in DNA damage manifested by single- and double-strand breaks (DSBs) in the sugar-phosphate backbone of the DNA molecule. Cross-links between DNA strands and chromosomal proteins also occur. The mechanism of DNA damage differs among the various radiation types.  Radiation damage is primarily manifested by the loss of cellular reproductive capacity, thus most cell types do not show morphologic evidence of radiation damage until they attempt to divide. Alternatively, some cell types are killed via the induction of apoptosis ¹⁶. Radiation also interacts directly with lipid and protein signaling pathways and modulates gene expression through a variety of mechanisms. Interaction with these signaling pathways can affect critical processes such as cell cycle regulation, DNA repair, apoptosis and tissue repopulation.

Other therapeutic approaches such as endocrine therapy and biological therapy are also important for specific tumor types. With the recent advancement in cancer genetics, agents have been developed in the last decade to specifically target one or a few key molecules. These agents are the basis of so-called targeted therapies ¹⁷. Small molecules inhibiting the proliferative signaling of the cancer cells and monoclonal antibodies against growth factor or vascular endothelial growth factor have been claimed as the latest promise in cancer therapy. For example, Imatinib, the first approved tyrosine kinase inhibitor, is effective to keep chronic myeloid leukemia (CML) from progression in 90% patients ¹⁸. Imatinib functions by blocking the ATP binding pocket on the BCR-ABL kinase, which is the major oncogenic molecule in CML ¹⁸. Another example of targeted therapy is herceptin. Herceptin is the FDA-approved therapeutic monoclonal antibody against HER2 and has been used to treat over 150,000 women with breast cancer ¹⁹. HER2 is amplified in roughly 18% to 20% of breast cancer patients and plays a key role in the pathogenesis of breast cancer, thus it represents an attractive therapeutic target. Other targeted therapeutics against HER receptors, such as Iressa and Tarceva that are small molecules, have also been tested in breast cancer ¹⁹. Although targeted cancer therapy has gained initial success against several malignant diseases, drug resistance is not an unusual event and may be intrinsic or developed during the treatment because of redundant signaling input from connected pathways. On the other hand, tumors harbor multiple genetic alterations, which require targeting several pathways to attack to achieve clinical effectiveness. Therefore, multi-targeting and combination therapy is conceivably a more effective strategy to suppress cancer.

DRUG RESISTANCE

Development of chemoresistance is a persistent problem during the treatment of local and disseminated malignant disease ²⁰. Cytotoxic drugs target actively proliferating cells. Inherent and acquired resistance pathways account for the high rate of failure in cancer chemotherapy ²¹. Principal mechanisms for chemoresistance may include altered membrane transport involving the P-glycoprotein product of the multidrug resistance (MDR) gene as well as other associated proteins, altered target enzyme, decreased drug activation, increased drug degradation due to altered expression of drug-metabolizing enzymes, drug inactivation, subcellular redistribution, drug-drug interaction, enhanced DNA repair and failure to apoptosis as a result of mutated cell cycle proteins such as p53. The resistant phenotype is usually characterized by alterations in multiple pathways.

Targeted tumor therapy is based on deregulated signaling in cancer. However, a limited number of somatic mutations have been identified and cancer cells may evade successful therapy due to mutation of the target protein or to resistance mechanisms acting downstream of or parallel to the therapeutic block. To improve therapy and molecular diagnostics, detailed information is needed on the pathway components that lead to the malignant phenotype. Recently, functional approaches based on RNA interference have been used to elucidate critical nodes in oncogenic signaling and the targets essential for malignancy ²².

Attempts to overcome resistance mainly involve combination drug therapy using different classes of drugs with minimally overlapping toxicities to allow maximal dosages and with narrowest cycle intervals, which is necessary for bone marrow recovery. Adjuvant therapy with P-glycoprotein inhibitors may represent another approach to abrogate or delay resistance.