Cancer as Pathological Repair: When Repair Becomes the Disease (Part 2)
Once the idea of cancer as a non-healing wound is taken seriously, a subtle but profound shift occurs. The question is no longer simply why cancer grows, but why the tissue environment never stabilizes. Growth, inflammation, vascular remodeling, and immune infiltration are not foreign processes imposed by cancer cells; they are native programs of repair. The mystery is not their presence, but their persistence.
Harold Dvorak’s original observation—that tumors resemble wounds that do not heal—was grounded in pathology. Tumors looked like granulation tissue: highly vascular, inflamed, and structurally disorganized. What was missing in 1986 was the molecular language to explain how this state could be indefinitely maintained.
That language now exists. Cancer biology has increasingly revealed that tumors are not isolated masses of malignant cells, but self-reinforcing tissue ecosystems in which repair programs are continuously re-initiated but never completed. In this sense, cancer can be understood as pathological repair: healing mechanisms activated in the wrong context, sustained beyond their normal endpoint, and co-opted to support malignancy
Table of Contents:
The Tumor Microenvironment as a Wound Bed
Modern oncology recognizes that cancer cells account for only a fraction of a tumor’s mass. The remainder consists of immune cells, fibroblasts, endothelial cells, extracellular matrix, signaling molecules, and metabolites. Collectively, this is known as the tumor microenvironment.
From a wound-healing perspective, the tumor microenvironment looks less like abnormal tissue and more like a permanent wound bed.
Inflammatory cytokines such as TNF-α, IL-6, and IL-1β are abundant. Growth factors including VEGF, PDGF, and TGF-β circulate at high levels. Matrix metalloproteinases continuously remodel the extracellular matrix. New blood vessels form—but remain tortuous and leaky. Immune cells are present, yet fail to clear the lesion.
These are not cancer-specific inventions. They are standard components of tissue repair.
The difference is that in normal wounds, these signals decay. In tumors, they do not.
Fibroblasts: From Repair Cells to Structural Enablers of Cancer
Fibroblasts play a central role in wound healing. Upon injury, they migrate into damaged tissue, proliferate, and deposit provisional extracellular matrix. This matrix provides scaffolding for cell migration and angiogenesis. Once repair is complete, fibroblasts deactivate or undergo apoptosis.
In tumors, fibroblasts often fail to deactivate. Instead, they differentiate into cancer-associated fibroblasts (CAFs)—cells that resemble fibroblasts trapped in a perpetual repair state.
CAFs secrete growth factors, cytokines, and extracellular matrix components that support tumor growth, invasion, and immune exclusion. They stiffen the tissue mechanically, alter metabolic gradients, and create physical barriers to immune cell infiltration and drug delivery.
Importantly, CAFs are not malignant. They are repair cells that never received the signal to stop.
This mirrors chronic wounds, where fibroblasts remain activated but ineffective, producing disorganized matrix that impedes closure rather than enabling it.
Angiogenesis Without Maturation
Angiogenesis is essential for both wound healing and tumor growth. In normal repair, new blood vessels sprout rapidly to supply oxygen and nutrients. Once tissue integrity is restored, these vessels regress or mature into stable structures.
Tumor vasculature, by contrast, remains permanently immature. Vessels are leaky, poorly aligned, and inefficient. Hypoxia persists despite high vessel density. This paradox—abundant blood vessels with poor oxygen delivery—is a hallmark of both tumors and chronic wounds.
From the wound perspective, this represents angiogenesis without resolution.
Rakesh Jain’s work on vascular normalization demonstrated that this abnormality is not inevitable. By partially inhibiting angiogenic signaling rather than abolishing it, tumor vessels can be coaxed toward a more normal structure, improving perfusion and immune access (Science, 2005).
This finding only makes sense if angiogenesis is understood not as a cancer-specific aberration, but as a repair program stuck in an early phase.
Immune Infiltration Without Clearance
Tumors are not immunologically silent. They are infiltrated by macrophages, neutrophils, T cells, dendritic cells, and other immune populations. Yet immune clearance fails.
In wound healing, immune cells play two critical roles: they eliminate pathogens and debris, and they coordinate the transition to resolution. Macrophages, in particular, shift phenotypes over time, moving from inflammatory to reparative states.
In tumors, macrophages are abundant but dysfunctional. Tumor-associated macrophages often resemble inflammatory or suppressive phenotypes that sustain tissue remodeling while inhibiting effective immune attack. Rather than resolving injury, they perpetuate it.
This pattern again mirrors chronic wounds, where macrophages fail to complete efferocytosis and remain locked in inflammatory states.
The presence of immune cells without resolution is not evidence of immune failure alone. It is evidence of misdirected repair biology.
Extracellular Matrix: Provisional Forever
The extracellular matrix (ECM) is not merely structural. It is a signaling platform that regulates cell behavior, migration, differentiation, and survival.
During wound healing, provisional ECM is laid down quickly and later remodeled into a stable, organized structure. This transition is essential for mechanical integrity and cellular quiescence.
Tumor ECM, like that of chronic wounds, remains provisional. It is dense, disorganized, and continuously remodeled. Matrix stiffness increases, altering mechanotransduction pathways that favor proliferation and invasion. Degradation products of ECM themselves act as inflammatory signals, further sustaining repair programs.
The tissue never settles.
Cancer Cells as Adaptive Participants, Not Sole Architects
Within this environment, cancer cells do not act alone. They adapt to and exploit the pathological repair state.
Cells that thrive under hypoxia, inflammation, oxidative stress, and mechanical distortion gain selective advantage. Traits such as metabolic flexibility, immune evasion, and resistance to apoptosis are rewarded.
From this perspective, malignancy emerges not only from genetic mutation, but from selection pressure imposed by unresolved injury.
This helps explain why identical mutations can behave differently in different tissues, and why aggressive therapies that intensify tissue damage can paradoxically accelerate resistance.
The environment is not a passive backdrop. It is an active participant.
Why Repair Cannot Resolve: The Missing Off-Switch
The central question, then, is not why repair programs activate in cancer—they are expected to—but why they cannot terminate.
One answer lies in persistent injury signals. As long as the tissue environment continues to experience molecular damage, repair programs are re-initiated. This creates a loop: injury begets repair; repair begets more injury.
Another answer lies in debris.
In normal healing, clearance of dead cells and damaged matrix is the signal that repair can end. When debris persists, the system interprets the tissue as still injured.
This sets the stage for the next essay, because it is here—at the level of unresolved debris—that the wound-cancer analogy becomes fully mechanistic rather than descriptive.
From Description to Causality
Dvorak’s formulation was prescient, but incomplete. He identified the phenotype of cancer as a non-healing wound. What he could not yet identify was the driver of non-healing.
Modern research suggests that the persistence of molecular debris—particularly DNA-based debris—may provide that driver. It is not merely that cancer looks like a wound; it may be kept alive by the same signals that indicate injury has not yet been repaired.
If that is true, then killing cancer cells without addressing debris risks perpetuating the very conditions that favor malignancy.
Why This Reframing Matters
Understanding cancer as pathological repair changes the therapeutic question. Instead of asking only how to eliminate malignant cells, we must also ask:
What signals tell tissue that injury is ongoing?
What prevents the transition to resolution?
How might therapy unintentionally reinforce non-healing states?
These questions are not philosophical. They are biological.
And they lead directly to the next problem: cell death itself may be one of the strongest drivers of persistent injury.
In the next essay, we will examine a deeply counterintuitive idea: that cell death is not always curative, and that under certain conditions, it may propagate damage, inflammation, and even malignancy.
To understand that, we must confront the biology of dying cells—not as endpoints, but as sources of signal.
Very good. What follows is Essay III, written at the same depth and pace as the prior two. This essay deliberately dismantles one of the most deeply embedded assumptions in oncology—that cell death is inherently beneficial—and replaces it with a biologically precise, evidence-based understanding of death as signal.
This is where the framework begins to feel unavoidable rather than speculative.