Function of oncogenes in cancer development: a changing paradigm

Abstract

Tumour-associated oncogenes induce unscheduled proliferation as well as genomic and chromosomal instability. According to current models, therapeutic strategies that block oncogene activity are likely to selectively target tumour cells. However, recent evidences have revealed that oncogenes are only essential for the proliferation of some specific tumour cell types, but not all. Indeed, the latest studies of the interactions between the oncogene and its target cell have shown that oncogenes contribute to cancer development not only by inducing proliferation but also by developmental reprogramming of the epigenome. This provides the first evidence that tumorigenesis can be initiated by stem cell reprogramming, and uncovers a new role for oncogenes in the origin of cancer. Here we analyse these evidences and propose an updated model of oncogene function that can explain the full range of genotype-phenotype associations found in human cancer. Finally, we discuss how this vision opens new avenues for developing novel anti-cancer interventions.

Figure 1

Examples of cancer types generated directly from mouse stem/progenitor cells by tumour fate reprogramming. Human cancer is associated to specific and consistent genetic events. Each one of these genetic defects is observed exclusively in characteristic subgroups of human cancer. In mouse models, as illustrated, specific genotype alterations associated to human cancer (medium circle) give rise to specific phenotypes (outer circle) when targeted to the stem cell/progenitor compartment (see text for details).

Figure 2

Proposed model for the role of human cancer gene defects in tumour cell fate specification. (A) Traditionally, the human cancer genetic defects have been thought to act on cells already committed to a differentiation program, in such a way that the tumoural phenotype is derived from that of the initial differentiated target cell. (B) Alternatively, the latest findings support a view in which the oncogenic lesion acts on stem/progenitor cells by imposing a given, oncogene-specific, tumour-differentiated cell fate.

Figure 3

Developmental biology of cancer cells. (A) Cancer cell-of-origin (or cancer-initiating cell): the cell where the first genetic lesion linked to the development of the tumour takes place. It might be located anywhere within the physiological differentiation pathway. It does not need to have any phenotypic relationship with the final phenotype of the tumour cells (either stem or differentiated). (B) CSC (cancer-maintaining cell): those cells that have the capacity to regenerate all the cellular diversity of the tumour. They retain broad self-renewal potential and differentiation potential. They arise initially from the cancer cell-of-origin, and then they can self-propagate. (C) Tumoural reprogramming: the process by which the initial oncogenic lesion(s) can ‘reset’ the epigenetic and/or transcriptome status of an initially healthy cell (the cancer cell-of-origin), therefore establishing a new, pathological differentiation program ultimately leading to cancer development, where the oncogenic lesion(s) does not need to be present anymore once the initial cancer fate-inducing change has taken place.

Figure 4

Tumour stem cell reprogramming versus reprogramming to pluripotency. (A) Recent in vivo genetic evidences have shown that human oncogenes are capable of reprogramming early stem/precursor cells towards specific differentiated tumour cell fates, but they are not required afterwards, within the malignant cells. (B) ‘Hit-and-run’ reprogramming has grounding in other contexts outside of cancer, such as during induced pluripotent stem (iPS) cell formation in vitro. However, unlike the tumour stem cell reprogramming, the iPS process initiates in a differentiated cell (see text for details).

Figure 5

Opportunities for therapeutic intervention using tumour stem cell reprogramming as a target. Tumour stem cell reprogramming largely relies on epigenetic modifications. These, unlike genetic changes, can be erased, manipulated, and reinitiated, therefore implying that anti-tumour reprogramming strategies can provide a new window of opportunity to interfere with the cancer fate-inducing change.