**9. VSELs and cancer**

80 Blood Cell – An Overview of Studies in Hematology

**functionality** 

**Figure 5.** Revised scheme for premeiotic development of germ cells in adult human testis

**8. Significance of somatic microenvironment 'Niche' on VSELs** 

changes and acquisition of errors during DNA replication.

which is more specialized and thus restricted in nature.

**Sr.no Tissue VSEL with** 

3 Bone marrow,

Umbilical cord blood and tissue

A relatively quiescent VSEL and actively dividing progenitor model that possibly exists in ovary, testis, bone marrow, cord blood and Wharton's jelly ensures that the 'master stem cell' undergoes very few rounds of DNA replication to prevent its genome from age-related

Table 3 highlights the importance of the somatic niche in controlling the stem cell fate. It is

1 Testis Adark spermatogonia stem cells SSCs (Adark)

**Table 3.** Details of Very Small Embryonic-Like Stem Cell–Derived Progenitors in Adult Human Tissues

The possible reason why extensive plasticity of VSELs is evident in bone marrow and cord blood (so many different kind of TCSCs have been described) in contrast to testis or ovary may be because the bone marrow niche is more permissive as compared to a 'gonadal' niche

Hematopoietic stem cells (HSC)

**Progenitor stem cells with cytoplasmic Oct-4** 

**(tissue-specific progenitor stem cells)** 

Mesenchymal stem cells (MSC)

the same VSEL that exists in different body organs but the niche dictates its fate [46].

**nuclear Oct-4** 

2 Ovary Ovarian germ stem cells (OGSCs)

Several years of cancer research suggests that cancers begin with genetic changes that occur over a period of 15 to 20 years and in few cases a link to chronic inflammation has been proposed e.g. in case of ovarian cancers, Barrett's esophagus etc. However, emerging literature suggests that quiescent VSELs distributed in various organs may be a cellular origin of cancer development. In 1855 Virchow proposed the embryonal rest hypothesis of tumor formation, based on histological similarities between tumors and embryonic tissues. This theory was later expanded by other pathologist including Julius Conheim, who suggested that tumors develop from residual embryonic remnants lost during developmental organogenesis [59]

Recently identified VSELs in various adult body tissues display morphology and markers characteristics as the pluripotent embryonic stem cells. These cells could support Virchow's concept of an embryonic origin of cancer. Possibly the somatic niche, which keeps the VSELs in a quiescent stage under normal circumstances, undergoes some changes which push the quiescent VSELs to an actively dividing state i.e. the tumor.

Wang et al [60] recently reported that persisting embryonic cells in adult mice and humans at the squamo-columnar junction are possibly the source of Barrett's metaplasia and that it does not arise from mutant cells. They proposed that certain precancerous lesions, such as Barrett's, initiate not from genetic alterations but from competitive interactions between cell lineages driven by opportunity. Similarly, almost 90% of ovarian cancers arise from the ovary surface epithelium which is also the niche for ovarian stem cells. It is being proposed that ovarian niche gets compromised with age leading to menopause [61, 62] and also to cancer. It is essential to dissect out age related changes which lead to menopause and how they differ from those which lead to cancer. OCT-4, characteristic marker of VSELs is also a very good marker with high sensitivity and specificity for testicular germ cell tumors as well [63].

Cancer stem cells and VSELs with embryonic characteristics have a lot of similarities in terms of markers, telomere length, and resistance to radiotherapy; thus it may be proposed that VSELs transform into CSCs when certain not so well understood changes occur in the microenvironment. It is possible that inflammation may alter the niche where the VSELs reside. It is highly unlikely that a somatic cell which is relatively senescent and has short telomeres will dedifferentiate and acquire long telomeres to transform into a cancer stem cell. Keeping this in mind, because of a defect in stem cell in the bone marrow due to an altered niche – defective stem cell divisions occur and differentiation of such altered cells results in appearance of chromosomal defects in mononuclear cells picked by standard cytogenetic studies.

Identification of VSELs in adult tissues also opens new areas of investigation to elucidate how these cells contribute to the development of poorly differentiated tumors. Studying the biology of normal stem cells may help us to better understand the biology of cancer, and explain its resistance to radio-chemotherapy, ability to an unlimited proliferation and establishment of distant metastases.
