Molecular Biology of Cancer Topics

Retinoids are a family of very lipophilic, natural and synthetic dietary compounds. After emulsification by with bile in the small intestine, retinoids are absorbed by diffusion and pakaged into chylomicrons. Chylomicron remanants enter the liver through receptor-mediated endocitosis. In the cytosol, retidoids combine with Cellular Retinoid Acid Binding Protein (CRABP). Finaly the are either stored in the liver as retinyl palmitate lipid droplets, or bind to their nuclear receptors, or are transfered in the Golgi to retinol-binding protein (1:1), which is the carried in the plasma by albumin.

Retinoids have several different function. In the retina (?) they act as a cofactor for the isomerizqation reaction of the photopigment rhodopsin. Gradients of retinoic acid are critical for pattern formation in development. RAR activates the expression of Hox genes, which in turn govern developmental processes.

Finally, retinoid acid treatment causes some cancerous cells to differentiate and stop dividing (Drach et al. Induction of differentiation of myeloid leukemia
cell lines and acute promyelocytic leukemia cells by liposomal all-trans retinoic acid. Cancer Res. 53; 2100-2104, 1993) .

The retinoic acid receptors, RARs and RXRs, are transcription factors in the steroid receptor superfamily. RAR a, b and g bind all-trans retinoic acid. RXR a, b and g bind 9-cis retinoic acid. RXR forms homodimers or heterodimers with the RAR or other steroid receptor, like the thyroid hormone receptor or the vitamin D receptor. Retinoid acid receptors bin to the retinoic acid receptor response elemnt (RARE) in DNA: AGGTCA(N)AGGTCA.

Hematopoiesis

Blood cells develop from the hematopoietic stem cell through a series of stages towards differentiation to the final phenotypes: erythrocytes, granular leukocytes (eosinophils, neutrophils and basophils), agranular leukocytes (monocytes and lymphocytes) or platelets. Granular leukocytes come from a commmon progenitor cell, the myeloblast, while erythrocytes come from proerythroblasts, monocytes from monoblasts, lymphocytes from lymphoblasts, and platelets from megakaryoblasts.

In a normal peripheral blood smear, there are relatively few white blood cells (leukocytes). Leukemia (cancer of the bone marrow) causes an increase in the numbers of leukocytes in the peripheral blood. How do you distinguish this from simple inflammation? Notice that all of the stages of the maturing white cells are present rather than just the mature (or nearly mature) forms. In general, malignant cells are less differentiated than normal cells.

Experimental Results:

The “differentiation block” of acute promyelocytic leukemia can be alleviated with retinoic acid (drug name Tretinoin). [Warrel et al. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N. Engl. J. Med. 324; 1385-1393, 1991]

Acute promyelocytic leukemia (APL) is characterized by a “differentiation block” of hematopoietic precursor cells at the promyelocyte stage. Life threating coagulopathy can occur. APL is due to a chromosomal translocation in >95% of cases, t(15;17) (q22;q12-21), that gives rice to the PML-RARa fusion gene and protein.

PML is at ranscription factor. The PML-RARa fusion protein dimerizes with PML but not with RARa.
PML is thought to be a growth suppressor/ tumor suppressor (?), with a final effect on cell proliferation similar to p53 (Mu et al. PML, a growth suppressor disrupted in acute promyelocytic leukemia. Mol. Cell. Biol. 14: 6858-6867, 1994).

PML growth suppressing activity is blocked by PML-RARa. PML-RARa may inhibit PML function, probably by sequstrating PML and preventing its transcriptional effects.

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