Cell death was first described in rabbit ovaries (Graaffian follicles), the phenomenon being called 'chromatolysis' rather than apoptosis. In humans, the ovarian endowment of primordial follicles is established during fetal life. Apoptotic cell death depletes this endowment by at least two-thirds before birth, executed with the help of several players and pathways conserved from worms to humans. To date, apoptosis has been reported to be involved in oogenesis, folliculogenesis, oocyte loss/selection and atresia. Several pro-survival and pro-apoptotic molecules are involved in ovarian apoptosis with the delicate balance between them being the determinant for the final destiny of the follicular cells. This review critically analyses the current knowledge about the biological roles of these molecules and their relevance to the dynamics of follicle development. It also presents the existing literature and assesses the gaps in our knowledge.

Every living organism on the surface of the earth is exposed to the ultraviolet (UV) fraction of the sunlight. This electromagnetic energy has both life-giving and life-endangering effects. UV radiation can damage DNA and thus mutagenize several genes involved in the development of the skin cancer. The presence of typical signature of UV-induced mutations on these genes indicates that the ultraviolet-B part of sunlight is responsible for the evolution of cutaneous carcinogenesis. During this process, variable alterations of the oncogenic, tumor-suppressive, and cell-cycle control signaling pathways occur. These pathways include (a) mutated PTCH (in the mitogenic Sonic Hedgehog pathway) and mutated p53 tumor-suppressor gene in basal cell carcinomas, (b) an activated mitogenic ras pathway and mutated p53 in squamous cell carcinomas, and (c) an activated ras pathway, inactive p16, and p53 tumor suppressors in melanomas. This review presents background information about the skin optics, UV radiation, and molecular events involved in photocarcinogenesis.

Skin metastasis is defined as the spread of malignant cells from a primary malignancy to the skin. It is one manifestation of systemic spread of cancer. The tumor cells originate either from an internal malignancy or from a primary skin cancer. This study presents a literature review concerning these issues as well as this author's experience encountered throughout 19 years of surgical pathology and dermatopathology practice. Several conclusions are evident. Generally, skin metastases are encountered in 0.7-9% of all patients with cancer and as such the skin is an uncommon site of metastatic disease when compared to other organs. There is usually a long-time lag between the diagnosis of the primary malignancy and the recognition of the skin metastases. However, these metastases may be the first indication of the clinically silent visceral malignancies. The regional distribution of the skin metastasis, although not always predictable, is related to the location of the primary malignancy and the mechanism of metastatic spread. The relative frequency of skin metastasis correlates with the type of primary cancer, which occurs in each sex. For instance, lung and breast carcinomas are the most common primaries that send skin metastasis in men and women, respectively. The head and neck region and the anterior chest are the areas of greatest predilection in men. The anterior chest wall and the abdomen are the most commonly involved sites in women. Skin metastases usually appear as non-specific groups of discrete firm painless nodules that emerge rapidly without any explanation. They vary in size from so tiny as to be of 'miliary lesions' to as large as 'Hen's egg size'. Some skin metastasis may mimic specific dermatological conditions such as cutaneous cyst, dermatofibroma, pyogenic granuloma, hemangioma, papular eruptions, herpes zoster eruptions, rapidly infiltrating plaques, alopecic patches, cellulitis and erysipelas. Histologically, the skin metastases usually show features reminiscent of the primary malignancy, but with variable degrees of differentiation. Molecularly, skin metastasis is an organized, non-random and organ-selective process orchestrated by interaction among several heterogeneous molecules, which are largely unknown. Metastasis to the skin is often a pre-terminal event that heralds poor outcome.

Melanoma cells can undergo self-destruction via programmed cell death, i.e. apoptosis. In these tumours, the molecular components of apoptosis include positive (apoptotic) and negative (anti-apoptotic) regulators. The former include p53, Bid, Noxa, PUMA, Bax, TNF, TRAIL, Fas/FasL, PITSLRE, interferons, and c-KIT/SCF. The latter include Bcl-2, Bcl-X(L), Mcl-1, NF-(K)B, survivin, livin, and ML-IAP. Alternatively, some molecules such as TRAF-2, c-Myc, endothelins, and integrins may have either pro- or anti-apoptotic effects. Some of these molecules are of potential therapeutic use, such as: (1) p53, which influences resistance to chemotherapy; (2) Mcl-1 and Bcl-X(L), which can override apoptosis; (3) TRAIL, which has selective fatal effects on tumour cells; (4) NF-(K)B, which when downregulated sensitizes cells to TRAIL and TNF; (5) the PITSLRE kinases, whose alteration appears to result in Fas resistance; (6) interferons, which sensitize cells to other factors; and (7) survivin and other IAPs that inhibit apoptosis. This review summarizes the state of current knowledge about the key molecular components and mechanisms of apoptosis in melanoma, discusses potential therapeutic ramifications, and provides directions for future research.

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