Abstract
Based on compelling evidence from many biological disciplines, we put forth a hypothesis for cancer metastasis. In the hypothesis, the metastatic cascade is depicted as human reproduction in miniature. Illustrated in a reproductive light, the staggering resemblance of cancer metastasis to human reproduction becomes evident despite some ostensible dis-similarities. In parallel to the appearance of primordial germ cells during early embryogenesis, the cancer reproductive saga starts with the separation of metastasis initiating cells (MICs) from cancer initiating cells when the primary cancer is still in its infancy. Prime MICs embark on a journey to the host bone marrow where they undergo further development and regulation. Migrating MICs are guided by the same CXCR4/CYCL12 axis as used in the migration of primordial germ cells to the genital ridge. Like the ovary, the host bone marrow features immune privileges, coolness, hypoxia and acidity which are essential for stemness maintenance and regulation. Opportune activation of the MICs via fusion with bone marrow stem cells triggers a frenzy of cellular proliferation and sets them on the move again. This scenario is akin to oocyte fertilization in the Fallopian tube and its subsequent journey towards the decidum. Just as the human reproductive process is plagued with undesirable outcomes so is the cancer metastasis highly inefficient. The climax of the cancer metastatic drama (colonization) is reached when proliferating MIC clusters attempt to settle down on decidum-like premetastatic sites. Successfully colonized clusters blossom into overt macrometastases only after the execution of sophisticated immunomodulation, angiogenesis and vascular remodeling. Similarly, the implanted blastomere needs to orchestrate these feats before flourishing into a new life. What is more, the cancer reproductive drama seems to be directed by a primordial hypothalamus–pituitary–gonad axis. Pursuing this reproductive trail could lead to new frontiers and breakthroughs in cancer research and therapeutics.
Highlights
Despite decades of global efforts, cancer still remains one of the major human killers
It is estimated that more than 90% of cancer related deaths are due to metastases rather primary cancers [1]
The linear and parallel hypotheses represent the two prevailing metastasis theories [6]. They converge on a multistep process and an evolutionary theme, but differ on the timeframe when it occurs in reference to the ontogeny of the primary tumor. The former stipulates that metastasis occurs at a late stage when a fittest subclone develops as a result of selection pressure
Summary
Despite decades of global efforts, cancer still remains one of the major human killers. The linear and parallel hypotheses represent the two prevailing metastasis theories [6] They converge on a multistep process and an evolutionary theme, but differ on the timeframe when it occurs in reference to the ontogeny of the primary tumor. The former stipulates that metastasis occurs at a late stage when a fittest subclone develops as a result of selection pressure. The latter argues for an early metastatic event and parallel evolution of the primary and metastatic cancer. In accordance with the parallel theory, we put forth this hypothesis of cancer metastasis in hopes of furthering cancer research and expediting the development of efficacious anti-metastasis therapeutics
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