SPECIAL ARTICLECancer and Pregnancy: Parallels in Growth, Invasion, and Immune Modulation and Implications for Cancer Therapeutic Agents
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SHARED CHARACTERISTICS OF TROPHOBLAST CELLS AND TUMOR CELLS
Five days after fertilization, the human zygote forms into a structure consisting of 2 primary cell lines: the inner cellmass (or embryoblast) and the trophoblast.3 Trophoblast cells constitute the outer layer of the blastocyst, rapidly proliferating and invading the maternal endometrial decidua around day 7. A monolayer of cytotrophoblast cells surrounds the embryonic disc as the embryo completely embeds beneath the uterine decidua. By day 9, cytotrophoblast cells have differentiated into 2
PROLIFERATION
Like tumor cells, trophoblast cells have a very high proliferative capacity and exhibit molecular characteristics found in rapidly dividing cancer cells.54 For example, increased telomerase activity, typically not observed to a substantial degree in normal somatic cells, is detectable in 85% of human cancers.55 In fact, the intracellular concentration of telomerase is exponentially related to the proliferative capacity of a cell.56 In human pregnancy, telomerase activity is highest during the
INVASION
The sine qua non of both a successful pregnancy and the growth of cancer is the establishment of a blood and nutrient supply, and invasion through normal tissues is required for this process. However, whereas cancer cells spread throughout the host and then engage in local proliferation, trophoblasts follow an organized pattern of differentiation from proliferation to invasion without distant metastasis.72 Some of the molecular switches involved in this differentiation pattern and their
VASCULOGENIC MIMICRY
As trophoblasts invade maternal spiral arteries, they further differentiate to display a vascular phenotype in a process termed vasculogenic mimicry, in which cells other than endothelial cells form vascular structures.97 Vasculogenic mimicry can also be observed in aggressive cancers, and the genes and signaling pathways involved with the process of vasculogenic mimicry may be shared between EVT and cancer cells.98 For example, the matrix glycoprotein—binding galectin 3 is highly expressed in
ANGIOGENESIS
Molecular circuits involved in neoangiogenesis separate from vasculogenic mimicry are also likely shared between EVT and tumor cells. Angiopoietins and VEGF family members are extremely important in both spiral artery remodeling in placentation106 and the growth of many tumor types.107 Inhibition of VEGF has become an important therapeutic strategy in many cancers, although resistance can develop,108 resulting from the induction of an angiogenic rescue program characterized by the up-regulation
IMMUNOLOGIC PROPERTIES OF THE FETOMATERNAL INTERFACE AND TUMOR MICROENVIRONMENT
In addition to sharing many proliferative and invasive features, the cells of the trophoblast, like cancer cells, actively modulate the host immune response to develop and sustain a nutrient supply. Historically, the placenta was considered an inert, mechanical barrier protecting the semiallogeneic fetus from maternal immunologic attack.119 Current evidence, however, supports just the opposite—many maternal and placental immunomodulatory factors are required for adequate placental invasion.
EVIDENCE FOR SYSTEMIC IMMUNE MODULATION
Similar to the increasing antigenic burden of progressive cancer,214 fetal DNA can be found circulating in maternal blood by the second trimester in the height of the tolerogenic cytokine milieu.215 Although its immunologic consequences have not been fully elucidated, this circulating DNA likely contributes to tolerance and eventual exhaustion of antigen-specific CTLs. This phenomenon is well described for the human immunodeficiency virus, chronic infection with which leads to progressive
IMPLICATIONS FOR CANCER THERAPEUTICS
As a healthy pregnancy progresses toward parturition, several changes within the mother reflect a restoration of active, TH1-predominant immunity. Although Treg levels stay constant until the postpartum period,252 a gradual return of CD16+ NK cells is observed in late pregnancy.253 Suppressed earlier in pregnancy, circulating cytotoxic γδ-T cells increase with the onset of labor.254 Interleukin 2 levels decrease while granulocyte macrophage colony—stimulating factor and interferon-γ increase
CONCLUSION
By comparing immunologic patterns throughout healthy pregnancies, and in particular the return to TH1-polarized immunity through the third trimester, with those patterns observed in advanced malignancies, we have an opportunity to learn potential mechanisms to overcome the burden of long-term antigenic exposure and immunologic exhaustion in patients with cancer. The challenge for investigators in this field will be to extend our observations beyond the TH1/TH2 paradigm in both pregnancy and
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A glossary of genetics terminology appears at the end of this article.