Cell biology of cancer

Cell biology of cancer: Protooncogenes are cellular genes that are normally involved in cell division, cell differentiation and cell death. Mutations in protooncogenes may convert them to oncogenes which cause dysregulated growth , differentiation and cell death leading to cancers (oncogenesis). These mutations can cause a hyperactive gene , mutations in the promoter region cause activation of transcription, gene amplification and translocations causing increased expression (like Philadelphia chromosome). Mutations in tumor suppressor genes that lead to loss of function can cause cancer. In contrast to oncogenes, tumor suppressor genes repress cell growth and division. Both copies of the tumor suppressor gene have to be mutated or lost (behave recessively), for oncogenesis whereas mutation in only one copy of the protooncogene (behaves in a dominant fashion), is needed for oncogenesis.

MicroRNAs or miRNAs are small, single stranded, endogenous RNAs 21-25 nucleotides in length. They are coded by non-coding/intron regions of the genes and are not transcribed into proteins. Upregulation or down-regulation of miRNAs occurs in various human cancers. miRNAs affect the expression of oncogenes and tumor suppressor genes. They bind to target mRNAs, resulting in translational repression and gene silencing.

Accumulation of genetic mutations over a period of time and DNA damage eventually causes cancer. The clonal evolution model of oncogenesis states that accumulated mutations within a single genetically transformed cell confers oncogenic potential and it eventually multiplies to form a clone of cancer cells. Such cells become insensitive to growth inhibitory signals, resist apoptosis and can sustain their growth with angiogenesis, invasion and metastases. The stem cell theory of cancer states that cancers arise from stem cells, which are self-renewing, more aggressive and resistant to therapy.

Undifferentiated tumor cells are less cohesive. During tumor invasion, E-cadherin is downregulated, tumor cells separate from the primary tumor, degrade the extracellular matrix by secreting enzymes like matrix metalloproteinases and collagenases and enter blood vessels and lymphatics, to be carried to distant sites. Angiogenesis or new blood vessel formation is accomplished by the secretion of VEGF which allows the tumor cells to grow. Circulating tumor cells may aggregate to form tumor emboli. Extravasation of tumor cells is aided by metalloproteinases and permeability protein angiopoeitin-like4. Some tumors express chemokine receptors like CXCR4 which help them localize to favorable organs rich in specific receptor ligands. The primary tumor primes other body tissues for tumor seeding by secreting favorable growth factors like VEGF and TGF beta. Micrometastases are small numbers of cancer cells that have spread from the primary tumor to other parts of the body and are too few to be picked up in a screening or diagnostic test. They are associated with a higher risk of recurrence.

Tumor grading and staging: Tumor grading is a measure of differentiation of tumor cells. Higher the grade, more undifferentiated the tumor is. Differentiated tumors look similar to their cell and tissue of origin while undifferentiated/anaplastic tumors do not. Grading is done by tumor biopsy. Following grades are reported:

GX: Grade cannot be assessed (undetermined grade)

G1: Well differentiated (low grade)

G2: Moderately differentiated (intermediate grade)

G3: Poorly differentiated (high grade)

G4: Undifferentiated (high grade)

Tumors with higher grades are more aggressive and spread faster. The Gleason scoring system is used to grade prostate cancer. A score <6 is well differentiated while a score >8 is poorly differentiated.

Tumor stage, on the other hand, determines the extent of spread of a tumor. It has a role in predicting prognosis and making appropriate therapeutic decisions. The TNM system is most commonly used.

T for tumor size and extent (TXM for main tumor cannot be measured; T0 for main tumor cannot be found, and T1, T2, T3, T4 for progressively increase in size.

N for presence or absence of lymph node metastases (NX, N0, N1,2 or 3).

M for distant metastases (MX, M0 and M1).

Stage 0: Abnormal cells are present but have not spread to nearby tissue. Also called carcinoma in situ, or CIS.

Stage I, Stage II, and Stage III: The higher the number, the larger the tumor and the more it has spread into nearby tissues.

Stage IV: The cancer has spread to distant parts of the body.