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Tumor Progression

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Tumor progression is a phenomenon where the pre-formed tumor acquires successive morphological and molecular changes to become more aggressive and malignant in its character.

Cancer begins as a single genetic change in a healthy cell, and with time, the progenies of that cell continue to proliferate and pass on the mutation to all the daughter cells. The genome of these mutant cells becomes increasingly unstable, allowing more mutations to accumulate.

For instance, in the initial stages of Chronic Myelogenous Leukemia or CML, the mutant cells exhibit a chromosomal aberration called the Philadelphia chromosome, which is formed by a reciprocal translocation, where the parts of chromosomes 22 and 9 swap places.

This creates a fusion protein BCR-ABL1 that helps cells increase the cell division rates, escape terminal differentiation, and avoid apoptosis, resulting in the accumulation of abnormal cells.

As the tumor progresses, the tumor cells stimulate the formation of new blood vessels around them by a process called angiogenesis.

These new blood vessels supply the cancer cells with oxygen, nutrients, and growth factors for rapid growth and proliferation. They also help the cancer cells to disseminate and travel to distant parts of the body and metastasize.

The parallel progression model best explains the tumor progression. According to this model, the breast cancer cells from the primary tumor, which is as small as 1 - 4 mm, can start to disseminate to distant organs and seed new tumors.

For the next 6 - 12 years, these seeds develop into secondary tumors in a parallel manner, each acquiring unique mutations at much faster rates. Such random mutations increase the chance of acquiring resistance to cancer treatment, jeopardizing the patients’ life.

Overview

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Tumor progression is a phenomenon where the pre-formed tumor acquires successive mutations to become clinically more aggressive and malignant. In the 1950s, Foulds first described the stepwise progression of cancer cells through successive stages.

Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further mutations in K-ras and p53 genes trigger the progress of a benign tumor into a malignant tumor. At the advanced stages of tumor progression, mutations in DCC and other related genes may contribute to tissue invasion and metastasis.

Biological changes

As the cancer cells progress, they tend to escape the cell cycle regulation and increase their growth rate. However, such cells do not divide faster than usual. They merely continue to divide uncontrollably without undergoing terminal differentiation and apoptosis. In other words, the cell cycle in such cells skips the resting G0 phase and progresses directly from the M phase to the G1 phase. Cancer cells also overcome contact inhibition, a property of normal cells to stop cell division upon coming in contact with other cells. This allows cancer cells to pile up on top of one another, forming a tumor mass.

Molecular changes

In the 1990s, sophisticated molecular biology tools identified three important gene groups that play a critical role in cancer progression. The first group includes genes involved in cell growth and survival. The second group comprises genes involved in maintaining genetic stability, such as DNA repair enzymes. The third group of genes is involved in tissue invasion and metastasis; examples include the genes encoding cell adhesion proteins, proteolytic enzymes, and angiogenesis factors. However, no single gene is found mutated in every human cancer.

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Tumor Progression

Cancer Cell Mutation

Cell Cycle Regulation

Contact Inhibition

Genetic Stability

Tissue Invasion